U.S. patent application number 11/426657 was filed with the patent office on 2006-12-21 for phenethanolamine derivatives for treatment of respiratory diseases.
This patent application is currently assigned to Glaxo Group Limited. Invention is credited to Keith BIGGADIKE, Diane Mary Coe, Dean David Edney, Stephen Barry Guntrip, Abigail Halton, Brian Edgar Looker, Michael John Monteith, Rebecca Jane Moore, Rajnikant Patel, Panayiotis Alexandrou Procopiou.
Application Number | 20060287389 11/426657 |
Document ID | / |
Family ID | 26245711 |
Filed Date | 2006-12-21 |
United States Patent
Application |
20060287389 |
Kind Code |
A1 |
BIGGADIKE; Keith ; et
al. |
December 21, 2006 |
PHENETHANOLAMINE DERIVATIVES FOR TREATMENT OF RESPIRATORY
DISEASES
Abstract
The present invention relates to novel compounds of Formula (I),
to a process for their manufacture, to pharmaceutical compositions
containing them, and to their use in therapy, in particular their
use in the prophylaxis and treatment of respiratory diseases.
Inventors: |
BIGGADIKE; Keith;
(Stevenage, GB) ; Coe; Diane Mary; (Stevenage,
GB) ; Edney; Dean David; (Dartford, GB) ;
Guntrip; Stephen Barry; (Stevenage, GB) ; Halton;
Abigail; (Dartford, GB) ; Looker; Brian Edgar;
(Stevenage, GB) ; Monteith; Michael John;
(Dartford, GB) ; Moore; Rebecca Jane; (Dartford,
GB) ; Patel; Rajnikant; (Dartford, GB) ;
Procopiou; Panayiotis Alexandrou; (Stevenage, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B475
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Assignee: |
Glaxo Group Limited
Greenford
GB
|
Family ID: |
26245711 |
Appl. No.: |
11/426657 |
Filed: |
June 27, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10467733 |
Feb 9, 2004 |
|
|
|
PCT/EP02/01387 |
Feb 11, 2002 |
|
|
|
11426657 |
Jun 27, 2006 |
|
|
|
Current U.S.
Class: |
514/540 ;
514/171; 514/602; 560/61; 564/86 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
25/24 20180101; A61P 43/00 20180101; A61P 11/02 20180101; C07C
2601/14 20170501; A61P 15/06 20180101; C07C 311/29 20130101; C07C
311/58 20130101; A61P 9/04 20180101; C07C 2601/04 20170501; A61P
17/06 20180101; C07C 311/27 20130101; C07D 295/26 20130101; A61P
17/00 20180101; A61P 11/00 20180101; C07D 295/13 20130101; A61P
27/14 20180101; A61P 21/00 20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/540 ;
564/086; 560/061; 514/602; 514/171 |
International
Class: |
C07C 311/02 20060101
C07C311/02; A61K 31/24 20060101 A61K031/24; A61K 31/18 20060101
A61K031/18; A61K 31/573 20060101 A61K031/573 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 14, 2001 |
GB |
0103630.0 |
Nov 9, 2001 |
GB |
0126998.4 |
Claims
1-15. (canceled)
16.
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-
-amino)heptyl]oxy}propyl)benzenesulfonamide, or a salt or solvate
thereof.
17. A compound according to claim 16, wherein the salt or solvate
is pharmaceutically acceptable.
18. A compound according to claim 16, wherein the compound is in
the form of a salt formed with a pharmaceutically acceptable acid
selected from cinnamic, substituted cinnamic, triphenylacetic,
sulphamic, sulphanilic, naphthaleneacrylic, benzoic,
4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and
4-phenylbenzoic acid.
19. A compound according to claim 16 which is
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide 4-phenylbenzoate.
20. A compound according to claim 16 which is
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide triphenylacetate.
21. A compound according to claim 16 which is
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide 4-phenylcinnamate.
22. A compound according to claim 16 which is
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide sulphamate.
23. A compound according to claim 16 which is
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide sulphanilate.
24. A method for the prophylaxis or treatment of a clinical
condition in a mammal, for which a selective 2-adrenoreceptor
agonist is indicated, which comprises administrating a
therapeutically effective amount of a compound according to claim
17.
25. A method according to claim 24, wherein the mammal is a
human.
26. A method according to claim 24, wherein the clinical condition
is asthma.
27. A method according to claim 24, wherein the clinical condition
is COPD.
28. A pharmaceutical formulation comprising a compound according to
claim 16 or a pharmaceutically acceptable salt or solvate thereof,
and a pharmaceutically acceptable carrier or excipient, and
optionally one or more other therapeutic ingredients.
29. A combination comprising a compound according to claim 16 or a
pharmaceutically acceptable salt or solvate thereof, and one or
more other therapeutic ingredients.
30. A combination according to claim 29 wherein the other
therapeutic ingredient is a PDE4 inhibitor or an anticholinergic or
a corticosteroid.
31. A combination according to claim 29 wherein the other
therapeutic ingredient is
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester.
32.
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-
-amino)heptyl]oxy}propyl)benzenesulfonamide
(E)-3-(napthalen-2-yl)-2-propenoate.
33. A method for the prophylaxis or treatment of a clinical
condition in a mammal, for which a selective
.beta..sub.2-adrenoreceptor agonist is indicated, which comprises
administrating a therapeutically effective amount of a compound
according to claim 32.
34. A method according to claim 33, wherein the mammal is a
human.
35. A method according to claim 33, wherein the clinical condition
is asthma.
36. A method according to claim 33, wherein the clinical condition
is COPD.
37. A pharmaceutical formulation comprising a compound according to
claim 32 or a pharmaceutically acceptable salt or solvate thereof,
and a pharmaceutically acceptable carrier or excipient, and
optionally one or more other therapeutic ingredients.
38. A combination comprising a compound according to claim 32 or a
pharmaceutically acceptable salt or solvate thereof, and one or
more other therapeutic ingredients.
39. A combination according to claim 38 wherein the other
therapeutic ingredient is a PDE4 inhibitor or an anticholinergic or
a corticosteroid.
40. A combination according to claim 38 wherein the other
therapeutic ingredient is
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester.
Description
[0001] The present invention is concerned with phenethanolamine
derivatives, processes for their preparation, compositions
containing them and their use in medicine, particularly in the
prophylaxis and treatment of respiratory diseases.
[0002] Certain phenethanolamine compounds are known in the art as
having selective stimulant action at .beta..sub.2-adrenoreceptors
and therefore having utility in the treatment of bronchial asthma
and related disorders. Thus GB 2 140 800 describes phenethanolamine
compounds including
4-hydroxy-.alpha..sup.1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl-
]-1,3-benzenedimethanol 1-hydroxy-2-naphthalenecarboxylate
(salmeterol xinafoate) which is now used clinically in the
treatment of such medical conditions.
[0003] Although salmeterol and the other commercially available
.beta..sub.2-adrenoreceptor agonists are effective bronchodilators,
the maximum duration of action is 12 hours, hence twice daily
dosing is often required. There is therefore a clinical need for
compounds having potent and selective stimulant action at
.beta..sub.2-adrenoreceptors and having an advantageous profile of
action.
[0004] According to the present invention, there is provided a
compound of formula (I) ##STR1## or a salt, solvate, or
physiologically functional derivative thereof, wherein: m is an
integer of from 2 to 8; n is an integer of from 3 to 11, preferably
from 3 to 7; with the proviso that m+n is 5 to 19, preferably 5 to
12; [0005] R.sup.1 is --XSO.sub.2NR.sup.6R.sup.7 wherein X is
--CH.sub.2).sub.p-- or C.sub.2-6 alkenylene; R.sup.6 and R.sup.7
are independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C(O)NR.sup.8R.sup.9, phenyl, and phenyl
(C.sub.1-4alkyl)-, or R.sup.6 and R.sup.7, together with the
nitrogen to which they are bonded, form a 5-, 6-, or 7-membered
nitrogen containing ring, and R.sup.6 and R.sup.7 are each
optionally substituted by one or two groups selected from halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6alkoxy,
hydroxy-substituted C.sub.1-6alkoxy, --CO.sub.2R.sup.8,
--SO.sub.2NR.sup.8R.sup.9, --CONR.sup.8R.sup.9,
--NR.sup.8C(O)R.sup.9, or a 5-, 6- or 7-membered heterocylic ring;
R.sup.8 and R.sup.9 are independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl, phenyl, and phenyl
(C.sub.1-4alkyl)-; and p is an integer of from 0 to 6, preferably
from 0 to 4; R.sup.2 and R.sup.3 are independently selected from
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, halo, phenyl, and
C.sub.1-6haloalkyl; and R.sup.4 and R.sup.5 are independently
selected from hydrogen and C.sub.1-4alkyl with the proviso that the
total number of carbon atoms in R.sup.4 and R.sup.5 is not more
than 4.
[0006] In the compounds of formula (I) the group R.sup.1 is
preferably attached to the meta-position relative to the
--O--(CH.sub.2).sub.n-- link.
R.sup.1 preferably represents --SO.sub.2NR.sup.6R.sup.7 wherein
R.sup.6 and R.sup.7 are independently selected from hydrogen and
C.sub.1-6alkyl, more preferably R.sup.1 is --SO.sub.2NH.sub.2.
R.sup.4 and R.sup.5 are preferably independently selected from
hydrogen and methyl, more preferably R.sup.4 and R.sup.5 are both
hydrogen.
m is suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6.
Preferably m is 5 or 6 and n is 3 or 4, such that m+n is 8, 9 or
10, preferably 9.
[0007] According to a preferred aspect of the invention, there is
provided a compound of formula (Ia) ##STR2## or a salt, solvate, or
physiologically functional derivative thereof, wherein R.sup.1 is
as defined above for formula (I).
[0008] According to a further preferred aspect of the invention,
there is provided a compound of formula (Ib) ##STR3## or a salt,
solvate, or physiologically functional derivative thereof, wherein
R.sup.1 is as defined above for formula (I).
[0009] In the compounds of formulae (Ia) and (Ib), the group
R.sup.1 is preferably attached to the meta-position relative to the
--O--(CH.sub.2).sub.n--, --O--(CH.sub.2).sub.4-- or
--O--(CH.sub.2).sub.3-- link respectively.
[0010] In the compounds of formulae (Ia) and (Ib), R.sup.1 is
preferably --SO.sub.2NR.sup.6R.sup.7 wherein R.sup.6 and R.sup.7
are independently selected from hydrogen and C.sub.1-6alkyl, more
preferably R.sup.1 is --SO.sub.2NH.sub.2.
[0011] It is to be understood that the present invention covers all
combinations of particular and preferred groups described
hereinabove.
[0012] Preferred compounds of the invention include: [0013]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)benzenesulfonamide; [0014]
4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)benzenesulfonamide; [0015]
2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)benzenesulfonamide; [0016]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-N-methylbenzenesulfonamide; [0017]
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-yl
sulfonyl)-phenyl]butoxy}hexyl)amino]ethyl}phenol; [0018]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamide; [0019]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide; [0020]
N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)ph-
enyl]-ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0021]
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperidin-1-ylsulfonyl)p-
henyl]-butoxy}hexyl)amino]ethyl}phenol; [0022]
1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)-hexyl]oxy}butyl)phenyl]methanesulfonamide; [0023]
3-(5-{[5-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)pentyl]oxy}pentyl)benzenesulfonamide; [0024]
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide; [0025]
3-{6-[4-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amin-
o)butoxy]hexyl}benzenesulfonamide; [0026]
4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamide; [0027]
3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}pentyl)benzenesulfonamide; [0028]
3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}hexyl)benzenesulfonamide; [0029]
3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}propyl)benzenesulfonamide; [0030]
3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)pentyl]oxy}butyl)benzenesulfonamide; [0031]
1-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)phenyl]methanesulfonamide; [0032]
1-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)phenyl]methanesulfonamide; [0033]
N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd-
roxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
[0034]
N-Benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]e-
thyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0035]
4-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]butoxy}-
-hexyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzene;
[0036]
3-(4-{[6-(f{2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)he-
xyl]oxy}butyl)benzenesulfonamide; [0037]
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)hexyl]oxy}butyl)benzenesulfonamide; [0038]
N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]et-
hyl}-amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamide
[0039]
N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen-
yl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0040]
N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen-
yl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0041]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
[0042]
N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hy-
droxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
[0043]
N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymeth-
yl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0044]
N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd-
roxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;
[0045]
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)p-
henyl]butoxy}hexyl)amino]ethyl}phenol; [0046]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamide;
[0047]
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}ami-
no)hexyl]oxy}butyl)-2-methoxybenzenesulfonamide; [0048]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)-5-pentylbenzenesulfonamide; [0049]
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]eth-
yl}-amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide; [0050]
2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)phenyl]ethanesulfonamide; [0051]
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)hexyl]oxy}butyl)[1,1'-biphenyl]-3-sulfonamide; [0052]
3-Fluoro-5-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]e-
thyl}amino)hexyl]oxy}butyl)benzenesulfonamide; [0053]
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)hexyl]oxy}butyl)-3-trifluoromethylbenzenesulfonamide; [0054]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)hexyl]oxy}butyl)-5-methylbenzenesulfonamide acetate [0055]
N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-
amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycine; [0056]
N.sup.2-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-
ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamide; and salts,
solvates, and physiologically functional derivatives thereof.
[0057] Particularly preferred compounds of the invention include:
[0058]
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-am-
ino)hexyl]oxy}butyl)benzenesulfonamide; [0059]
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)hexyl]oxy}butyl)benzenesulfonamide; [0060]
3-(4-{[6-({(2R/S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-a-
mino)hexyl]oxy}butyl)benzenesulfonamide; [0061]
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide; [0062]
3-(3-{[7-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-ami-
no)heptyl]oxy}propyl)benzenesulfonamide; [0063]
3-(3-{[7-({(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-a-
mino)heptyl]oxy}propyl)benzenesulfonamide; and salts, solvates, and
physiologically functional derivatives thereof.
[0064] Of these compounds,
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}ami-
no)hexyl]oxy}butyl)benzenesulfonamide and
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amin-
o)heptyl]oxy}propyl)benzenesulfonamide are especially
preferred.
[0065] In the definition of R.sup.1 where `R.sup.6 and R.sup.7
together with the nitrogen atom to which they are bonded, form a
5-, 6-, or 7-membered nitrogen containing ring`, the term "5-, 6-,
or 7-membered nitrogen containing ring" means a 5-, 6-, or
7-membered saturated or unsaturated ring which includes the
sulfonamide nitrogen atom and optionally 1 or 2 other heteroatoms
independently selected from nitrogen, sulphur, and oxygen. Suitable
examples of such a ring include piperidinyl, morpholinyl, and
piperazinyl.
[0066] In the definition of R.sup.1, specifically the optional
substituents on R.sup.6 and R.sup.7, the term "5-, 6-, or
7-membered heterocyclic ring" means a 5-, 6-, or 7-membered fully
or partially saturated or unsaturated ring which includes 1, 2, 3
or 4 heteroatoms independently selected from nitrogen, sulphur, and
oxygen. Suitable examples of such a ring include pyrrolyl, furyl,
thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl,
tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl, piperidinyl,
morpholinyl, and piperazinyl.
[0067] In the definition of X, the term "alkenylene" includes both
cis and trans structures. Suitable examples of alkenylene groups
include --CH.dbd.CH--.
[0068] The compounds of formulae (I), (Ia) and (Ib) include an
asymmetric centre, namely the carbon atom of the ##STR4## group.
The present invention includes both (S) and (R) enantiomers either
in substantially pure form or admixed in any proportions.
[0069] Similarly, where R.sup.4 and R.sup.5 are different groups,
the carbon atom to which they are attached is an asymmetric centre
and the present invention includes both (S) and (R) enantiomers at
this centre either in substantially pure form or admixed in any
proportions.
[0070] Thus the compounds of formulae (I), (Ia) and (Ib) include
all enantiomers and diastereoisomers as well as mixtures thereof in
any proportions.
[0071] Salts and solvates of compounds of formulae (I), (Ia) and
(Ib) which are suitable for use in medicine are those wherein the
counterion or associated solvent is pharmaceutically acceptable.
However, salts and solvates having non-pharmaceutically acceptable
counterions or associated solvents are within the scope of the
present invention, for example, for use as intermediates in the
preparation of other compounds of formulae (I), (Ia) and (Ib) and
their pharmaceutically acceptable salts, solvates, and
physiologically functional derivatives.
[0072] By the term "physiologically functional derivative" is meant
a chemical derivative of a compound of formula (I), (Ia) or (Ib)
having the same physiological function as the parent compound of
formula (I), (Ia) or (Ib), for example, by being convertible in the
body thereto.
[0073] According to the present invention, examples of
physiologically functional derivatives include esters.
[0074] Suitable salts according to the invention include those
formed with both organic and inorganic acids or bases.
Pharmaceutically acceptable acid addition salts include those
formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric,
phosphoric, lactic, pyruvic, acetic, trifluoroacetic,
triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric,
maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic,
ethanesulphonic, arylsulphonic (for example p-toluenesulphonic,
benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic),
salicylic, glutaric, gluconic, tricarballylic, cinnamic,
substituted cinnamic (for example, phenyl, methyl, methoxy or halo
substituted cinnamic, including 4-methyl and 4-methoxycinnamic
acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1-
or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example
naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or
4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic
(for example 1,4-benzenediacrylic) and isethionic acids.
Pharmaceutically acceptable base salts include ammonium salts,
alkali metal salts such as those of sodium and potassium, alkaline
earth metal salts such as those of calcium and magnesium and salts
with organic bases such as dicyclohexyl amine and
N-methyl-D-glucamine.
[0075] Advantageously, preferred compounds of the invention such as
3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}ami-
no)hexyl]oxy}butyl)benzenesulfonamide and
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amin-
o)heptyl]oxy}propyl)benzenesulfonamide are provided in the form of
a crystalline salt, for example selected from those exemplified in
the experimental section below. Said crystalline salts have
favourable physical properties such as low hygroscopicity and/or
improved stability. Particularly preferred salts include the
cinnamate, 4-methoxycinnamate, 4-methylcinnamate,
naphthalenepropenoate and 4-phenylcinnamate salts.
[0076] Pharmaceutically acceptable esters of the compounds of
formulae (I), (Ia) and (Ib) may have a hydroxyl group converted to
a C.sub.1-6alkyl, aryl, aryl C.sub.1-6 alkyl, or amino acid
ester.
[0077] As mentioned above, the compounds of formulae (I), (Ia) and
(Ib) are selective .beta..sub.2-adrenoreceptor agonists as
demonstrated using functional or reporter gene readout from cell
lines transfected with human beta-adrenoreceptors as described
below. Compounds according to the present invention also have the
potential to combine long duration of effect with rapid onset of
action. Furthermore, certain compounds have shown an improved
therapeutic index in animal models relative to existing long-acting
.beta..sub.2-agonist bronchodilators. As such, compounds of the
invention may be suitable for once-daily administration.
[0078] Compounds of formulae (I), (Ia) and (Ib) and their
pharmaceutically acceptable salts, solvates, and physiologically
functional derivatives have use in the prophylaxis and treatment of
clinical conditions for which a selective
.beta..sub.2-adrenoreceptor agonist is indicated. Such conditions
include diseases associated with reversible airways obstruction
such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g.
chronic and wheezy bronchitis, emphysema), respiratory tract
infection and upper respiratory tract disease (e.g. rhinitis,
including seasonal and allergic rhinitis).
[0079] Other conditions which may be treated include premature
labour, depression, congestive heart failure, skin diseases (e.g.
inflammatory, allergic, psoriatic, and proliferative skin
diseases), conditions where lowering peptic acidity is desirable
(e.g. peptic and gastric ulceration) and muscle wasting
disease.
[0080] Accordingly, the present invention provides a method for the
prophylaxis or treatment of a clinical condition in a mammal, such
as a human, for which a selective .beta..sub.2-adrenoreceptor
agonist is indicated, which comprises administration of a
therapeutically effective amount of a compound of formula (I), (Ia)
or (Ib), or a pharmaceutically acceptable salt, solvate, or
physiologically functional derivative thereof. In particular, the
present invention provides such a method for the prophylaxis or
treatment of a disease associated with reversible airways
obstruction such as asthma, chronic obstructive pulmonary disease
(COPD), respiratory tract infection or upper respiratory tract
disease. In a further aspect the present invention provides such a
method for the prophylaxis or treatment of a clinical condition
selected from premature labour, depression, congestive heart
failure, skin diseases (e.g. inflammatory, allergic, psoriatic, and
proliferative skin diseases), conditions where lowering peptic
acidity is desirable (e.g. peptic and gastric ulceration) or muscle
wasting disease.
[0081] In the alternative, there is also provided a compound of
formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt,
solvate, or physiologically functional derivative thereof for use
in medical therapy, particularly, for use in the prophylaxis or
treatment of a clinical condition in a mammal, such as a human, for
which a selective .beta..sub.2-adrenoreceptor agonist is indicated.
In particular, there is provided a compound of formula (I), (Ia) or
(Ib) or a pharmaceutically acceptable salt, solvate, or
physiologically functional derivative thereof for the prophylaxis
or treatment of a disease associated with reversible airways
obstruction such as asthma, chronic obstructive pulmonary disease
(COPD), respiratory tract infection or upper respiratory tract
disease. In a further aspect, there is provided a compound of
formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt,
solvate, or physiologically functional derivative thereof for the
prophylaxis or treatment of a clinical condition selected from
premature labour, depression, congestive heart failure, skin
diseases (e.g. inflammatory, allergic, psoriatic, and proliferative
skin diseases), conditions where lowering peptic acidity is
desirable (e.g. peptic and gastric ulceration) or muscle wasting
disease.
[0082] The present invention also provides the use of a compound of
formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt,
solvate, or physiologically functional derivative thereof in the
manufacture of a medicament for the prophylaxis or treatment of a
clinical condition for which a selective
.beta..sub.2-adrenoreceptor agonist is indicated, for example a
disease associated with reversible airways obstruction such as
asthma, chronic obstructive pulmonary disease (COPD), respiratory
tract infection or upper respiratory tract disease. In a further
aspect, there is provided a compound of formula (I), (Ia) or (Ib),
or a pharmaceutically acceptable salt, solvate, or physiologically
functional derivative thereof in the manufacture of a medicament
for the prophylaxis or treatment of a clinical condition selected
from premature labour, depression, congestive heart failure, skin
diseases (e.g. inflammatory, allergic, psoriatic, and proliferative
skin diseases), conditions where lowering peptic acidity is
desirable (e.g. peptic and gastric ulceration) and muscle wasting
disease.
[0083] The amount of a compound of formula (I), (Ia) or (Ib), or a
pharmaceutically acceptable salt, solvate or physiologically
functional derivative thereof which is required to achieve a
therapeutic effect will, of course, vary with the particular
compound, the route of administration, the subject under treatment,
and the particular disorder or disease being treated. The compounds
of the invention may be administered by inhalation at a dose of
from 0.0005 mg to 10 mg, preferably 0.005 mg to 0.5 mg. The dose
range for adult humans is generally from 0.0005 mg to 100 mg per
day and preferably 0.01 mg to 1 mg per day.
[0084] While it is possible for the compound of formula (I), (Ia)
or (Ib), or a pharmaceutically acceptable salt, solvate, or
physiologically functional derivative thereof to be administered
alone, it is preferable to present it as a pharmaceutical
formulation.
[0085] Accordingly, the present invention further provides a
pharmaceutical formulation comprising a compound of formula (I),
(Ia) or (Ib) or a pharmaceutically acceptable salt, solvate, or
physiologically functional derivative thereof, and a
pharmaceutically acceptable carrier or excipient, and optionally
one or more other therapeutic ingredients.
[0086] Hereinafter, the term "active ingredient" means a compound
of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable
salt, solvate, or physiologically functional derivative
thereof.
[0087] The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous
and intraarticular), inhalation (including fine particle dusts or
mists which may be generated by means of various types of metered
dose pressurised aerosols, nebulisers or insufflators), rectal and
topical (including dermal, buccal, sublingual and intraocular)
administration although the most suitable route may depend upon for
example the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of
pharmacy. All methods include the step of bringing the active
ingredient into association with the carrier which constitutes one
or more accessory ingredients. In general the formulations are
prepared by uniformly and intimately bringing into association the
active ingredient with liquid carriers or finely divided solid
carriers or both and then, if necessary, shaping the product into
the desired formulation.
[0088] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as a solution or a
suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0089] A tablet may be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, lubricating, surface
active or dispersing agent. Moulded tablets may be made by moulding
in a suitable machine a mixture of the powdered compound moistened
with an inert liquid diluent. The tablets may optionally be coated
or scored and may be formulated so as to provide slow or controlled
release of the active ingredient therein.
[0090] Formulations for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents. The formulations may be
presented in unit-dose or multi-dose containers, for example sealed
ampoules and vials, and may be stored in a freeze-dried
(lyophilised) condition requiring only the addition of the sterile
liquid carrier, for example saline or water-for-injection,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0091] Dry powder compositions for topical delivery to the lung by
inhalation may, for example, be presented in capsules and
cartridges of for example gelatine, or blisters of for example
laminated aluminium foil, for use in an inhaler or insulator.
Formulations generally contain a powder mix for inhalation of the
compound of the invention and a suitable powder base (carrier
substance) such as lactose or starch. Use of lactose is preferred.
Each capsule or cartridge may generally contain between 20 .mu.g-10
mg of the compound of formula (I) optionally in combination with
another therapeutically active ingredient. Alternatively, the
compound of the invention may be presented without excipients.
Packaging of the formulation may be suitable for unit dose or
multi-dose delivery. In the case of multi-dose delivery, the
formulation can be pre-metered (eg as in Diskus, see GB 2242134 or
Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use
(eg as in Turbuhaler, see EP 69715). An example of a unit-dose
device is Rotahaler (see GB 2064336). The Diskus inhalation device
comprises an elongate strip formed from a base sheet having a
plurality of recesses spaced along its length and a lid sheet
hermetically but peelably sealed thereto to define a plurality of
containers, each container having therein an inhalable formulation
containing a compound of formula (I) preferably combined with
lactose. Preferably, the strip is sufficiently flexible to be wound
into a roll. The lid sheet and base sheet will preferably have
leading end portions which are not sealed to one another and at
least one of the said leading end portions is constructed to be
attached to a winding means. Also, preferably the hermetic seal
between the base and lid sheets extends over their whole width. The
lid sheet may preferably be peeled from the base sheet in a
longitudinal direction from a first end of the said base sheet.
[0092] Spray compositions for topical delivery to the lung by
inhalation may for example be formulated as aqueous solutions or
suspensions or as aerosols delivered from pressurised packs, such
as a metered dose inhaler, with the use of a suitable liquefied
propellant. Aerosol compositions suitable for inhalation can be
either a suspension or a solution and generally contain the
compound of formula (I) optionally in combination with another
therapeutically active ingredient and a suitable propellant such as
a fluorocarbon or hydrogen-containing chlorofluorocarbon or
mixtures thereof, particularly hydrofluoroalkanes, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon
dioxide or other suitable gas may also be used as propellant. The
aerosol composition may be excipient free or may optionally contain
additional formulation excipients well known in the art such as
surfactants eg oleic acid or lecithin and cosolvents eg ethanol.
Pressurised formulations will generally be retained in a canister
(eg an aluminium canister) closed with a valve (eg a metering
valve) and fitted into an actuator provided with a mouthpiece.
[0093] Medicaments for administration by inhalation desirably have
a controlled particle size. The optimum particle size for
inhalation into the bronchial system is usually 1-10 .mu.m,
preferably 2-5 .mu.m. Particles having a size above 20 .mu.m are
generally too large when inhaled to reach the small airways. To
achieve these particle sizes the particles of the active ingredient
as produced may be size reduced by conventional means eg by
micronisation. The desired fraction may be separated out by air
classification or sieving. Preferably, the particles will be
crystalline. When an excipient such as lactose is employed,
generally, the particle size of the excipient will be much greater
than the inhaled medicament within the present invention. When the
excipient is lactose it will typically be present as milled
lactose, wherein not more than 85% of lactose particles will have a
MMD of 60-90 .mu.m and not less than 15% will have a MMD of less
than 15 .mu.m.
[0094] Intranasal sprays may be formulated with aqueous or
non-aqueous vehicles with the addition of agents such as thickening
agents, buffer salts or acid or alkali to adjust the pH,
isotonicity adjusting agents or anti-oxidants.
[0095] Solutions for inhalation by nebulation may be formulated
with an aqueous vehicle with the addition of agents such as acid or
alkali, buffer salts, isotonicity adjusting agents or
antimicrobials. They may be sterilised by filtration or heating in
an autoclave, or presented as a non-sterile product.
[0096] Formulations for rectal administration may be presented as a
suppository with the usual carriers such as cocoa butter or
polyethylene glycol.
[0097] Formulations for topical administration in the mouth, for
example buccally or sublingually, include lozenges comprising the
active ingredient in a flavoured basis such as sucrose and acacia
or tragacanth, and pastilles comprising the active ingredient in a
basis such as gelatin and glycerin or sucrose an acacia.
[0098] Preferred unit dosage formulations are those containing an
effective dose, as hereinbefore recited, or an appropriate fraction
thereof, of the active ingredient.
[0099] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations of this invention
may include other agents conventional in the art having regard to
the type of formulation in question, for example those suitable for
oral administration may include flavouring agents.
[0100] The compounds and pharmaceutical formulations according to
the invention may be used in combination with or include one or
more other therapeutic agents, for example selected from
anti-inflammatory agents, anticholinergic agents (particularly an
M.sub.1, M.sub.2, M.sub.1/M.sub.2 or M.sub.3 receptor antagonist),
other .beta..sub.2-adrenoreceptor agonists, antiinfective agents
(e.g. antibiotics, antivirals), or antihistamines. The invention
thus provides, in a further aspect, a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt,
solvate or physiologically functional derivative thereof together
with one or more other therapeutically active agents, for example
selected from an anti-inflammatory agent (for example a
corticosteroid or an NSAID), an anticholinergic agent, another
.beta..sub.2-adrenoreceptor agonist, an antiinfective agent (e.g.
an antibiotic or an antiviral), or an antihistamine. Preferred are
combinations comprising a compound of formula (I) or a
pharmaceutically acceptable salt, solvate or physiologically
functional derivative thereof together with a corticosteroid,
and/or an anticholinergic, and/or a PDE-4 inhibitor. Preferred
combinations are those comprising one or two other therapeutic
agents.
[0101] It will be clear to a person skilled in the art that, where
appropriate, the other therapeutic ingredient(s) may be used in the
form of salts, (e.g. as alkali metal or amine salts or as acid
addition salts), or prodrugs, or as esters (e.g. lower alkyl
esters), or as solvates (e.g. hydrates) to optimise the activity
and/or stability and/or physical characteristics (e.g. solubility)
of the therapeutic ingredient. It will be clear also that where
appropriate, the therapeutic ingredients may be used in optically
pure form.
[0102] Suitable anti-inflammatory agents include corticosteroids
and NSAIDs. Suitable corticosteroids which may be used in
combination with the compounds of the invention are those oral and
inhaled corticosteroids and their pro-drugs which have
anti-inflammatory activity. Examples include methyl prednisolone,
prednisolone, dexamethasone, fluticasone propionate,
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxy-androsta-1,4-diene-17.beta.-carbothioic acid
S-(2-oxo-tetrahydro-furan-3S-yl)ester, beclomethasone esters (e.g.
the 17-propionate ester or the 17,21-dipropionate ester),
budesonide, flunisolide, mometasone esters (e.g. the furoate
ester), triamcinolone acetonide, rofleponide, ciclesonide,
butixocort propionate, RPR-106541, and ST-126. Preferred
corticosteroids include fluticasone propionate,
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-[(-
4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17.beta.-ca-
rbothioic acid S-fluoromethyl ester and
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester, more preferably
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester.
[0103] Suitable NSAIDs include sodium cromoglycate, nedocromil
sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4
inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists,
inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and
elastase inhibitors, beta-2 integrin antagonists and adenosine
receptor agonists or antagonists (e.g. adenosine 2a agonists),
cytokine antagonists (e.g. chemokine antagonists) or inhibitors of
cytokine synthesis. Suitable other .beta..sub.2-adrenoreceptor
agonists include salmeterol (e.g. as the xinafoate), salbutamol
(e.g. as the sulphate or the free base), formoterol (e.g. as the
fumarate), fenoterol or terbutaline and salts thereof.
[0104] Of particular interest is use of the compound of formula (I)
in combination with a phosphodiesterase 4 (PDE4) inhibitor or a
mixed PDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in
this aspect of the invention may be any compound that is known to
inhibit the PDE4 enzyme or which is discovered to act as a PDE4
inhibitor, and which are only PDE4 inhibitors, not compounds which
inhibit other members of the PDE family as well as PDE4. Generally
it is preferred to use a PDE4 inhibitor which has an IC.sub.50
ratio of about 0.1 or greater as regards the IC.sub.50 for the PDE4
catalytic form which binds rolipram with a high affinity divided by
the IC.sub.50 for the form which binds rolipram with a low
affinity. For the purposes of this disclosure, the cAMP catalytic
site which binds R and S rolipram with a low affinity is
denominated the "low affinity" binding site (LPDE 4) and the other
form of this catalytic site which binds rolipram with a high
affinity is denominated the "high affinity" binding site (HPDE 4).
This term "HPDE4" should not be confused with the term "hPDE4"
which is used to denote human PDE4.
[0105] Initial experiments may be conducted to establish and
validate a [.sup.3H]-rolipram binding assay. Details of this work
are given in the Binding Assays described in detail below.
Phosphodiesterase and Rolipram Binding Assays
Assay method 1A
[0106] Isolated human monocyte PDE4 and hrPDE (human recombinant
PDE4) was determined to exist primarily in the low affinity form.
Hence, the activity of test compounds against the low affinity form
of PDE4 can be assessed using standard assays for PDE4 catalytic
activity employing 1 .mu.M [.sup.3H]cAMP as a substrate (Torphy et
al., J. of Biol. Chem., Vol. 267, No. 3 pp 1798-1804, 1992). Rat
brain high speed supernatants were used as a source of protein and
both enantiomers of [.sup.3H]-rolipram were prepared to a specific
activity of 25.6 Ci/mmol. Standard assay conditions were modified
from the published procedure to be identical to the PDE assay
conditions, except for the last of the cAMP: 50 mM Tris HCl (pH
7.5), 5 mM MgCl.sub.2, 50 .mu.M 5'-AMP and 1 nM of
[.sup.3H]-rolipram (Torphy et al., J. of Biol. Chem., Vol. 267, No.
3 pp 1798-1804, 1992). The assay was run for 1 hour at 30.degree.
C. The reaction was terminated and bound ligand was separated from
free ligand using a Brandel cell harvester. Competition for the
high affinity binding site was assessed under conditions that were
identical to those used for measuring low affinity PDE activity,
expect that [.sup.3H]-cAMP was not present.
Assay Method 1B
Measurement of Phosphodiesterase Activity
[0107] PDE activity was assayed using a [.sup.3H]cAMP SPA or
[.sup.3H]cGMP SPA enzyme assay as described by the supplier
(Amersham Life Sciences). The reactions were conducted in 96-well
plates at room temperature, in 0.1 ml of reaction buffer containing
(final concentrations): 50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl.sub.2,
1.7 mM EGTA, [.sup.3H]cAMP or [.sup.3H] cGMP (approximately 2000
dpm/pmol), enzyme and various concentrations of the inhibitors. The
assay was allowed to proceed for 1 hr and was terminated by adding
50 .mu.l of SPA yttrium silicate beads in the presence of zinc
sulfate. The plates were shaken and allowed to stand at room
temperature for 20 min. Radiolabeled product formation was assessed
by scintillation spectrometry.
[.sup.3H]R-rolipram Binding Assay
[0108] The [.sup.3H]R-rolipram binding assay was performed by
modification of the method of Schneider and co-workers, see
Nicholson, et al., Trends Pharmacol. Sci., Vol. 12, pp. 19-27
(1991) and McHale et al., Mol. Pharmacol., Vol. 39, 109-113 (1991).
R-Rolipram binds to the catalytic site of PDE4 see Torphy et al.,
Mol. Pharmacol., Vol. 39, pp. 376-384 (1991). Consequently,
competition for [.sup.3H]R-rolipram binding provides an independent
confirmation of the PDE4 inhibitor potencies of unlabeled
competitors. The assay was performed at 30.degree. C. for 1 hr in
0.5 .mu.l buffer containing (final concentrations): 50 mM Tris-HCl,
pH 7.5, 5 mM MgCl.sub.2, 0.05% bovine serum albumin, 2 nM
[.sup.3H]R-rolipram (5.7.times.104 dpm/pmol) and various
concentrations of non-radiolabeled inhibitors. The reaction was
stopped by the addition of 2.5 ml of ice-cold reaction buffer
(without [.sup.3H]--R-rolipram) and rapid vacuum filtration
(Brandel Cell Harvester) through Whatman GF/B filters that had been
soaked in 0.3% polyethylenimine. The filters were washed with an
additional 7.5 ml of cold buffer, dried, and counted via liquid
scintillation spectrometry. The preferred PDE4 inhibitors of use in
this invention will be those compounds which have a salutary
therapeutic ratio, i.e., compounds which preferentially inhibit
cAMP catalytic activity where the enzyme is in the form that binds
rolipram with a low affinity, thereby reducing the side effects
which apparently are linked to inhibiting the form which binds
rolipram with a high affinity. Another way to state this is that
the preferred compounds will have an IC.sub.50 ratio of about 0.1
or greater as regards the IC.sub.50 for the PDE4 catalytic form
which binds rolipram with a high affinity divided by the IC.sub.50
for the form which binds rolipram with a low affinity.
[0109] A further refinement of this standard is that of one wherein
the PDE4 inhibitor has an IC.sub.50 ratio of about 0.1 or greater;
said ratio is the ratio of the IC.sub.50 value for competing with
the binding of 1 nM of [.sup.3H]R-rolipram to a form of PDE4 which
binds rolipram with a high affinity over the IC.sub.50 value for
inhibiting the PDE4 catalytic activity of a form which binds
rolipram with a low affinity using 1 .mu.M [.sup.3H]-cAMP as the
substrate.
[0110] Examples of useful PDE4 inhibitors are: [0111]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone; [0112]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone; [0113]
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-5-methyl-isothiourei-
do]benzyl)-2-pyrrolidone; [0114] cis
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic
acid]; [0115]
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-
-ol]; [0116]
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]a-
cetate; and [0117]
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]a-
cetate.
[0118] Most preferred are those PDE4 inhibitors which have an
IC.sub.50 ratio of greater than 0.5, and particularly those
compounds having a ratio of greater than 1.0. Preferred compounds
are cis
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic
acid,
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cy-
clohexan-1-one and
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-
-ol]; these are examples of compounds which bind preferentially to
the low affinity binding site and which have an IC.sub.50 ratio of
0.1 or greater.
[0119] Other compounds of interest include:
[0120] Compounds set out in U.S. Pat. No. 5,552,438 issued 03
September, 1996; this patent and the compounds it discloses are
incorporated herein in full by reference. The compound of
particular interest, which is disclosed in U.S. Pat. No. 5,552,438,
is
cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyli-
c acid (also known as cilomalast) and its salts, esters, pro-drugs
or physical forms;
[0121] AWD-12-281 from Asta Medica (Hofgen, N. et al. 15th EFMC Int
Symp Med Chem (September 6-10, Edinburgh) 1998, Abst P.98; CAS
reference No. 247584020-9); a 9-benzyladenine derivative nominated
NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a
benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and
attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa
Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp
(Landells, L. J. et al. Eur Resp J [Annu Cong Eur Resp Soc
(September 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393);
roflumilast (CAS reference No 162401-32-3) and a pthalazinone
(WO99/47505, the disclosure of which is hereby incorporated by
reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,
10bS*)-9-ethoxy-1,2,3,4,4a,
10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-di
isopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has
been prepared and published on by Byk-Gulden, now Altana;
arofylline under development by Almirall-Prodesfarma; VM554/UM565
from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol
Exp Ther, 1998, 284(1): 162), and T2585.
[0122] Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include
those listed in WO01/13953, the disclosure of which is hereby
incorporated by reference.
[0123] Suitable anticholinergic agents are those compounds that act
as antagonists at the muscarinic receptor, in particular those
compounds which are antagonists of the M.sub.1 and M.sub.2
receptors.
[0124] Exemplary compounds include the alkaloids of the belladonna
plants as illustrated by the likes of atropine, scopolamine,
homatropine, hyoscyamine; these compounds are normally administered
as a salt, being tertiary amines. These drugs, particularly the
salt forms, are readily available from a number of commercial
sources or can be made or prepared from literature data via, to
wit:
Atropine--CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine
sulfate --CAS-5908-99-6;
atropine oxide --CAS-4438-22-6 or its HCl salt --CAS-4574-60-1 and
methylatropine nitrate--CAS-52-88-0.
Homatropine --CAS-87-00-3, hydrobromide salt --CAS-51-56-9,
methylbromide salt --CAS-80-49-9.
Hyoscyamine (d, l)-CAS-101-31-5, hydrobromide salt --CAS-306-03-6
and sulfate salt --CAS-6835-16-1.
Scopolamine--CAS-51-34-3, hydrobromide salt --CAS-6533-68-2,
methylbromide salt-CAS-155-41-9.
[0125] Preferred anticholinergics include ipratropium (e.g. as the
bromide), sold under the name Atrovent, oxitropium (e.g. as the
bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1).
Also of interest are: methantheline (CAS-53-46-3), propantheline
bromide (CAS-50-34-9), anisotropine methyl bromide or Valpin 50
(CAS-80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9),
copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8),
mepenzolate bromide (U.S. Pat. No. 2,918,408), tridihexethyl
chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate
(Tral, CAS-115-63-9). See also cyclopentolate hydrochloride
(CAS-5870-29-1), tropicamide (CAS-1508-75-4), trihexyphenidyl
hydrochloride (CAS-144-116), pirenzepine (CAS-29868-97-1),
telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the
compounds disclosed in WO01/04118, the disclosure of which is
hereby incorporated by reference.
[0126] Suitable antihistamines (also referred to as
H.sub.1-receptor antagonists) include any one or more of the
numerous antagonists known which inhibit H.sub.1-receptors, and are
safe for human use. All are reversible, competitive inhibitors of
the interaction of histamine with H.sub.1-receptors. The majority
of these inhibitors, mostly first generation antagonists, have a
core structure, which can be represented by the following formula:
##STR5##
[0127] This generalized structure represents three types of
antihistamines generally available: ethanolamines,
ethylenediamines, and alkylamines. In addition, other first
generation antihistamines include those which can be characterized
as based on piperizine and phenothiazines. Second generation
antagonists, which are non-sedating, have a similar
structure-activity relationship in that they retain the core
ethylene group (the alkylamines) or mimic the tertiary amine group
with piperizine or piperidine. Exemplary antagonists are as
follows:
Ethanolamines: carbinoxamine maleate, clemastine fumarate,
diphenylhydramine hydrochloride, and dimenhydrinate.
Ethylenediamines: pyrilamine amleate, tripelennamine HCl, and
tripelennamine citrate.
Alkylamines: chlropheniramine and its salts such as the maleate
salt, and acrivastine.
Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,
cyclizine lactate, meclizine HCl, and cetirizine HCl.
Piperidines: Astemizole, levocabastine HCl, loratadine or its
descarboethoxy analogue, and terfenadine and fexofenadine
hydrochloride or another pharmaceutically acceptable salt.
Azelastine hydrochloride is yet another H.sub.1 receptor antagonist
which may be used in combination with a PDE4 inhibitor.
[0128] Examples of preferred anti-histamines include methapyrilene
and loratadine.
[0129] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with a PDE4 inhibitor.
[0130] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with a corticosteroid.
[0131] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with an anticholinergic.
[0132] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with an antihistamine.
[0133] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with a PDE4 inhibitor and a corticosteroid.
[0134] The invention thus provides, in a further aspect, a
combination comprising a compound of formula (I) a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof together with an anticholinergic and a PDE-4 inhibitor.
[0135] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above together with a physiologically acceptable diluent or
carrier represent a further aspect of the invention.
[0136] The individual compounds of such combinations may be
administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations. Appropriate doses of known
therapeutic agents will be readily appreciated by those skilled in
the art.
[0137] According to a further aspect of the invention, there is
provided a process for preparing a compound of formula (I), (Ia) or
(Ib) or a salt, solvate, or physiologically functional derivative
thereof which comprises a process (a) (b) (c) or (d) as defined
below followed by the following steps in any order: [0138] (i)
optional removal of any protecting groups; [0139] (ii) optional
separation of an enantiomer from a mixture of enantiomers; [0140]
(iii) optional conversion of the product to a corresponding salt,
solvate, or physiologically functional derivative thereof.
[0141] In one general process (a), a compound of formula (I), (Ia)
or (Ib) may be obtained by deprotection of a protected
intermediate, for example of formula (II): ##STR6## or a salt or
solvate thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, m, and n are as defined for the compound of formula (I),
(Ia) or (Ib), R.sup.8, R.sup.9, and R.sup.10 are each independently
either hydrogen or a protecting group provided that at least one of
R.sup.8, R.sup.9, and R.sup.10 is a protecting group, and R.sup.14
is either hydrogen or a protecting group.
[0142] Suitable protecting groups may be any conventional
protecting group such as those described in "Protective Groups in
Organic Synthesis" by Theodora W Greene and Peter G M Wuts, 3rd
edition (John Wiley & Sons, 1999). Examples of suitable
hydroxyl protecting groups represented by R.sup.8 and R.sup.9 are
esters such as acetate ester, aralkyl groups such as benzyl,
diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples
of suitable amino protecting groups represented by R.sup.10 include
benzyl, .alpha.-methylbenzyl, diphenylmethyl, triphenylmethyl,
benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as
trichloroacetyl or trifluoroacetyl.
[0143] As will be appreciated by the person skilled in the art, use
of such protecting groups may include orthogonal protection of
groups in the compounds of formula (II) to facilitate the selective
removal of one group in the presence of another, thus enabling
selective functionalisation of a single amino or hydroxyl function.
For example, the --CH(OH) group may be orthogonally protected as
--CHOR.sup.14 using, for example, a trialkylsilyl group such as
triethylsilyl. A person skilled in the art will also appreciate
other orthogonal protection strategies, available by conventional
means as described in Theodora W Greene (see above).
[0144] The deprotection to yield a compound of formula (I), (Ia) or
(Ib) may be effected using conventional techniques. Thus, for
example, when R.sup.8, R.sup.9, and/or R.sup.10 is an aralkyl
group, this may be cleaved by hydrogenolysis in the presence of a
metal catalyst (e.g. palladium on charcoal).
[0145] When R.sup.8 and/or R.sup.9 is tetrahydropyranyl this may be
cleaved by hydrolysis under acidic conditions. Acyl groups
represented by R.sup.10 may be removed by hydrolysis, for example
with a base such as sodium hydroxide, or a group such as
trichloroethoxycarbonyl may be removed by reduction with, for
example, zinc and acetic acid. Other deprotection methods may be
found in Theodora W Greene (see above). In a particular embodiment
of process (a), R.sup.8 and R.sup.9 may together represent a
protecting group as in the compound of formula (III). ##STR7## or a
salt or solvate thereof, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.14, m, and n are as defined for the
compound of formula (I), (Ia) or (Ib), R.sup.11 and R.sup.12 are
independently selected from hydrogen, C.sub.1-6alkyl, or aryl. In a
preferred aspect, both R.sup.11 and R.sup.12 are methyl.
[0146] A compound of formula (III) may be converted to a compound
of formula (I), (Ia) or (Ib) by hydrolysis with dilute aqueous
acid, for example acetic acid or hydrochloric acid in a suitable
solvent or by transketalisation in an alcohol, for example ethanol,
in the presence of a catalyst such as an acid (for example,
toluenesulphonic acid) or a salt (such as pyridinium tosylate) at
normal or elevated temperature.
[0147] It will be appreciated that the protecting groups R.sup.8,
R.sup.9, R.sup.10 and R.sup.14 (including the cyclised protecting
group formed by R.sup.8 and R.sup.9 as depicted in formula (III)
may be removed in a single step or sequentially. The precise order
in which protecting groups are removed will in part depend upon the
nature of said groups and will be readily apparent to the skilled
worker. Preferably, when R.sup.8 and R.sup.9 together form a
protecting group as in formula (III) this protecting group is
removed together with any protecting group on the CH(OH) moiety,
followed by removal of R.sup.10.
[0148] Compounds of formulae (II) and (III) wherein R.sup.10 is
hydrogen may be prepared from the corresponding compound of formula
(IV): ##STR8## or a salt or solvate thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.8, R.sup.9 m, and n are
as defined for the compound of formula (II) or (III).
[0149] The conversion of a compound of formula (IV) to a compound
of formula (II) or (111) may be effected by treatment with a base,
for example a non-aqueous base, such as potassium
trimethylsilanoate, or an aqueous base such as aqueous sodium
hydroxide, in a suitable solvent such as tetrahydrofuran.
[0150] Compounds of formula (IV) may be prepared from the
corresponding compound of formula (V): ##STR9## or a salt or
solvate thereof, wherein R.sup.4, R.sup.5, R.sup.8, R.sup.9, m and
n are as defined for the compound of formula (IV); by coupling with
a compound of formula (VI): ##STR10## wherein R.sup.1, R.sup.2, and
R.sup.3 are as defined for the compound of formula (IV) and L is a
leaving group, such as a halo group (typically, bromo or iodo) or a
sulphonate ester such as a haloalkyl sulphonate (typically,
trifluoromethanesulphonate), followed by reduction.
[0151] The coupling of compound of formula (V) with a compound of
formula (VI) is conveniently effected in the presence of a catalyst
system such as bis(triphenylphosphine) palladium dichloride with an
organic base such as a trialkylamine, for example, triethylamine,
in a suitable solvent, for example acetonitrile or
dimethylformamide. The resulting alkyne may then be reduced, either
with or without being isolated to form the compound of formula
(IV). The reduction may be effected by any suitable method such as
hydrogenation in the presence of a catalyst, for example,
palladium/charcoal or platinum oxide.
[0152] Alternatively, in the compounds of formula (VI) R.sup.1,
R.sup.2, and R.sup.3 may represent groups convertible into R.sup.1,
R.sup.2, and R.sup.3, for example halo groups. This is particularly
useful where one of the groups R.sup.1, R.sup.2, and R.sup.3 may be
affected by any of the subsequent transformations. Thus, for
example, where R.sup.1 contains an alkenylene moiety, this is
preferably introduced after the reduction of the alkyne formed by
reaction of compounds (V) and (VI).
[0153] Compounds of formula (VI) are commercially available or may
be prepared by methods well known to the person skilled in the
art.
[0154] Compounds of formula (V) may be prepared by coupling a
compound of formula (VII): ##STR11## or a salt or solvate thereof,
wherein R.sup.8 and R.sup.9 are as defined for the compound of
formula (V) with a compound of formula (VIII):
L.sup.1CR.sup.4R.sup.5(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-2--C.ident.CH
(VII) wherein R.sup.4, R.sup.5, m and n are as defined for the
compound of formula (V) and L.sup.1 is a leaving group, for example
a halo group (typically bromo or iodo) or a sulphonate such as an
alkyl sulphonate (typically, methanesulphonate), an arylsulphonate
(typically, toluenesulphonate), or a haloalkyl sulphonate
(typically, trifluoromethanesulphonate).
[0155] The coupling of a compound of formula (VII) with a compound
of formula (VIII) may be effected in the presence of a base, such
as a metal hydride, for example sodium hydride, or an inorganic
base such as cesium carbonate, in an aprotic solvent, for example
dimethylformamide.
[0156] Compounds of formula (VIII) may be prepared from the
corresponding dihaloalkane and hydroxyalkyne by conventional
chemistry, typically in the presence of an inorganic base, such as
aqueous sodium hydroxide, under phase transfer conditions in the
presence of a salt such as tetraalkylammonium bromide.
[0157] Compounds of formula (VII) may be prepared by ring closure
of a compound of formula (IX): ##STR12## wherein R.sup.8 and
R.sup.9 are as defined for the compound of formula (VII) and
R.sup.13 is C.sub.1-6alkyl, for example tert-butyl, or aryl, for
example phenyl. The ring closure may be effected by treatment with
a base, such as a metal hydride, for example sodium hydride, in the
presence of an aprotic solvent, for example, dimethylformamide.
[0158] Compounds of formula (IX) may be prepared from the
corresponding ketone of formula (X): ##STR13## wherein R.sup.8 and
R.sup.9 and R.sup.13 are as defined for the compound of formula
(IX), by reduction by any suitable method, for example by treatment
with borane, in the presence of a chiral catalyst, such as
CBS-oxazaborolidine, in a suitable solvent such as
tetrahydrofuran.
[0159] The compound of formula (X) may be prepared from the
corresponding halide of formula (XI) ##STR14## wherein R.sup.8 and
R.sup.9 are as defined for the compound of formula (X) and Y is
halo, suitably bromo.
[0160] The conversion of a compound of formula (XI) to a compound
of formula (X) may be effected by reaction with the protected amine
HN(COOR.sup.13).sub.2 wherein R.sup.13 is as defined for the
compound of formula (X) in the presence of an inorganic base such
as cesium carbonate, followed by selective removal of one of the
COOR.sup.13 groups, for example by treatment with an acid such as
trifluoroacetic acid.
[0161] Compounds of formula (XI) may be prepared from the
corresponding compound having free hydroxymethyl and hydroxy
substituents (which itself may be prepared from 2-bromo-1-(4
hydroxy)-3-hydroxymethyl-phenethyl)ethanone, the preparation of
which is described in GB2140800, by treatment with 2-methoxypropane
in acetone in the presence of an acid e.g. p-toluene-sulphonic acid
in a nitrogen atmosphere or by other standard methods) by forming
the protected groups R.sup.8OCH.sub.2-- and R.sup.9O-- wherein
R.sup.8 and R.sup.9 are as defined for the compound of formula
(XI). Such methods are described in DE 3513885 (Glaxo).
[0162] Compounds of formula (II) or (III) wherein R.sup.10 is a
protecting group may be prepared as described in process (b) below,
or by analogous methods to process (c) below.
[0163] In a further process (b), a compound of formula (I), (Ia) or
(Ib) may be obtained by alkylation of an amine of formula (XII):
##STR15## wherein R.sup.8, R.sup.9, R.sup.10 and R.sup.14 are each
independently either hydrogen or a protecting group. Suitable
protecting groups are discussed in the definition of compounds of
formula (II);
[0164] with a compound of formula (XIII): ##STR16## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, m, and n are as
defined for the compound of formula (I), (Ia) or (Ib) and L.sup.2
is a leaving group such as halo (typically bromo); followed by
removal of any protecting groups present by conventional methods as
described above for the deprotection of compounds of formula
(II).
[0165] The reaction of compounds of formulae (XII) and (XIII) is
optionally effected in the presence of an organic base such as a
trialkylamine, for example, diisopropylethylamine, and in a
suitable solvent for example dimethyl formamide.
[0166] Compounds of formula (XII) are known in the art (for example
EP-A 0947498) or may be readily prepared by a person skilled in the
art.
[0167] Compounds of formula (XIII) may be prepared by coupling a
compound of formula (VI) as defined above, or a precursor thereof
(wherein one or more of the substituents R.sup.1, R.sup.2 or
R.sup.3 is a group which is convertible to the desired group
R.sup.1, R.sup.2, or R.sup.3) with a compound of formula (VIII) as
shown above wherein R.sup.4, R.sup.5, m, and n are as defined for
the compound of formula (XIII) and L.sup.1 is a leaving group as
defined above.
[0168] The coupling of a compound of formula (VIII) with a compound
(VI) may be effected by methods analogous to those described above
for coupling a compound of formula (V) with a compound of formula
(VI), followed by reduction of the resulting alkyne of formula
(XIV): ##STR17## also as described above. If necessary, the
substituents R.sup.1, R.sup.2, and/or R.sup.3 may be formed by
conventional conversions where a precursor is present.
[0169] An alkyne of formula (XIV) may also be prepared by reacting
a compound of formula (XV): L.sup.2CR.sup.4R.sup.5(CH.sub.2)m
L.sup.3 (XV) with a compound of formula (XVI): ##STR18## using
conventional methods, for example as described for the preparation
of compounds (VItl).
[0170] Compounds of formula (XVI) may be prepared by reacting a
hydroxyalkyne ##STR19## with a compound of formula (VI) using
methods analogous to those described above for coupling a compound
(V) with a compound (VI).
[0171] In a further process (c) a compound of formula (I), (Ia) or
(Ib) may be prepared by reacting a compound of formula (XVII):
##STR20## wherein R.sup.8, R.sup.9 and R.sup.14 are as hereinbefore
defined and L.sup.4 is a leaving group, is reacted with an amine of
formula (XVIII): ##STR21## followed by removal of any protecting
groups present by conventional methods as described above for the
deprotection of compounds of formula (II).
[0172] The reaction may be effected using conventional conditions
for such displacement reactions.
[0173] Compounds of formula (XVII) may be prepared by methods known
in the art.
[0174] Compounds of formula (XVIII) may be prepared by reacting a
compound of formula (XIII) with an amine R.sup.10NH.sub.2.
[0175] In a further process (d) a compound of formula (I), (Ia) or
(Ib) may be prepared by removal of a chiral auxiliary from a
compound of formula (IIa): ##STR22## wherein R.sup.1-R.sup.5,
R.sup.8, R.sup.9, m and n are as hereinbefore defined and R.sup.15
represents a chiral auxiliary.
[0176] A "chiral auxiliary" is a moiety that is introduced into a
molecule to influence the stereochemistry of the product formed,
and is removed in whole or part at a later time. A chiral auxiliary
may simultaneously function as a protecting group.
[0177] Many chiral auxiliaries are commercially available, and
persons skilled in the art would choose one based on the properties
desired i.e. the absolute stereochemistry desired and compatibility
with the processes being used. Chiral auxiliaries suitable for use
in this process include but are not limited to the S-isomer and/or
the R-isomer of phenyl glycinol and substituted derivatives
thereof.
[0178] The chiral auxiliary is preferably a moiety of the formula:
##STR23## or a single enantiomer thereof, wherein R.sup.16
represents C.sub.1-6alkyl or optionally substituted phenyl or
benzyl wherein the optional substitution is one or more
independently selected from C.sub.1-6alkyl, halogen, hydroxy,
C.sub.1-6alkoxy or nitro e.g. para-hydroxyphenyl.
[0179] More preferably the chiral auxiliary is a moiety: ##STR24##
wherein R.sup.16 is as defined above. Alternatively it may be a
moiety of formula: ##STR25## wherein R.sup.16 is as defined
above.
[0180] Preferably R.sup.16 represents phenyl optionally substituted
as described above, Most preferably R represents unsubstituted
phenyl.
[0181] The chiral auxiliary in this process may typically be
removed by hydrogenolysis using for example a palladium on carbon
catalyst or preferably using palladium hydroxide (Pearlman's
catalyst). Advantageously when Pearlman's catalyst is used the
removal of the chiral auxiliary is most efficient. This method of
removal is especially suitable where R.sup.1 is phenyl or a
substituted phenyl. Alternatively the nitrogen, to which the
auxiliary is attached, may be derivatised under oxidising
conditions to form the N-oxide before elimination by heating to
give a secondary amine.
[0182] A compound of formula (IIa) may be prepared by reduction of
the corresponding alkyne of formula (XIX): ##STR26##
[0183] Preferably in the compounds of formulae (IIa) and (XIX) the
protecting groups R.sup.8 and R.sup.9 together form a group
--CR.sup.11R.sup.12-- as in the compounds of formula (III).
[0184] Reduction of an alkyne of formula (XIX) may be effected by
methods well known in the art, for example by catalytic
hydrogenation, using palladium on charcoal or more preferably
palladium hydroxide (Pearlman's catalyst). The chiral auxiliary may
also be removed under reductive conditions. Advantageously,
therefore the reduction of the alkyne and removal of the chiral
auxiliary may be effected concomitantly in a `one-pot`
reaction.
[0185] An alkyne of formula (XIX) may be prepared by reaction of a
compound of formula (XX) ##STR27## with a compound of formula (VI)
under conditions described above for coupling of compounds (V) and
(VI).
[0186] A compound of formula (XX) may be prepared by reacting a
compound of formula (XIIa): ##STR28## with an aldehyde of formula
(XXI): ##STR29## using known methods for effecting reductive
amination, e.g. sodium triacetoxyborohydride in a solvent such as
chloroform
[0187] An aldehyde of formula (XXI) may be prepared from a
corresponding halide of formula (VIII) using standard techniques
such as treatment with sodium bicarbonate in a solvent such as DMSO
at elevated temperature, preferably in the range 130-160.degree.
C.
[0188] A compound of formula (XIIa) may be prepared from a compound
of formula (XXII): ##STR30##
[0189] Wherein R.sup.8, R.sup.9 and R.sup.15 are as hereinbefore
defined by treatment with a reducing agent such as a hydride source
e.g. sodium borohydride. Preferably this process takes place in the
presence of an inert metal salt such as calcium chloride suitably
at non-extreme temperatures e.g. below ambient, such as 0.degree.
C. This allows the desired stereochemistry to be introduced
efficiently with good enantiomeric excess at an early stage in the
synthesis, using inexpensive and relatively harmless reagents.
Furthermore, the enantiomeric excess may be increased by
recrystallisation of the product of this process.
[0190] A compound of formula (XXII) may be prepared from a compound
of formula (XI) as hereinbefore defined by reaction with an
appropriate chiral amine, e.g. (S)-phenylglycinol, in the presence
of a non-nucleophilic base in an inert solvent at non-extreme
temperatures.
[0191] A detailed description of a process analogous to Route (d)
may be found in published International Application Number
WO/0196278.
[0192] In the above process (d) it is preferred that the protecting
groups R.sup.8 and R.sup.9 together form a protecting group as
depicted in formula (III).
[0193] It will be appreciated that in any of the routes (a) to (d)
described above, the precise order of the synthetic steps by which
the various groups and moieties are introduced into the molecule
may be varied. It will be within the skill of the practitioner in
the art to ensure that groups or moieties introduced at one stage
of the process will not be affected by subsequent transformations
and reactions, and to select the order of synthetic steps
accordingly.
[0194] The enantiomeric compounds of the invention may be obtained
(i) by separation of the components of the corresponding racemic
mixture, for example, by means of a chiral chromatography column,
enzymic resolution methods, or preparing and separating suitable
diastereoisomers, or (ii) by direct synthesis from the appropriate
chiral intermediates by the methods described above.
[0195] Optional conversions of a compound of formula (I), (Ia) or
(Ib) to a corresponding salt may conveniently be effected by
reaction with the appropriate acid or base. Optional conversion of
a compound of formula (I), (Ia) or (Ib) to a corresponding solvate
or physiologically functional derivative may be effected by methods
known to those skilled in the art.
[0196] According to a further aspect, the present invention
provides novel intermediates for the preparation of compounds of
formula (I), (Ia) or (Ib), for example:
compounds of formula (II) and (III) as defined above, or an optical
isomer, a salt, or a protected derivative thereof; particularly, a
compound selected from:
[0197]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydro-
xyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; [0198]
4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}benzenesulfonamide; [0199]
2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}benzenesulfonamide; [0200]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-N-methylbenzenesulfonamide; [0201]
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(morpholin-4-yl-
sulfonyl)phenyl]butoxy}hexyl)amino]ethanol; [0202]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-N,N-dimethylbenzenesulfonamide; [0203]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-N-isopropylbenzenesulfonamide; [0204]
N-(tert-Butyl)-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; and [0205]
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperidin-1-yl-
sulfonyl)phenyl]butoxy}hexyl)amino]ethanol; [0206]
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperazin-1-yl-
sulfonyl)phenyl]butoxy}hexyl)amino]ethanol; [0207]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]--
amino}hexyl)oxy]butyl}-N-(1-methyl-1-phenylethyl)benzenesulfonamide;
[0208]
N-[4-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,-
3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamid-
e; [0209]
{3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4-H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-
]-amino}hexyl)oxy]butyl}phenyl}methanesulfonamide; [0210]
5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-2-methoxybenzenesulfonamide; [0211]
3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]--
amino}pentyl)oxy]pentyl}benzenesulfonamide; [0212]
3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]--
amino}heptyl)oxy]propyl}benzenesulfonamide; [0213]
3-[6-(4-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-a-
mino}butoxy)hexyl]benzenesulfonamide; [0214]
3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]propyl}benzenesulfonamide; [0215]
3-{4-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}pentyl)oxy]butyl}benzenesulfonamide; [0216]
N-[3-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzod-
ioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
[0217]
N-Benzyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; [0218]
3-{4-[(6-{[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}-
hexyl)oxy]butyl}benzenesulfonamide; [0219]
3-{4-[(6-{[(2S)-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]ami-
no}hexyl)oxy]butyl}benzenesulfonamide; [0220]
N-(4-{[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydrox-
yethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]amino}phenyl)acetamide;
[0221]
N-Cyclobutyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-
-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;
[0222]
N-Cyclohexyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-h-
ydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide; [0223]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-N-(4-fluorophenyl)benzenesulfonamide; [0224]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}-hexyl)oxy]butyl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
[0225]
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide;
[0226]
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)ethenesulfonamide;
[0227]
5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}[1,1'-biphenyl]-3-sulfonamide; [0228]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}-5-pentylbenzenesulfonamide; compounds of
formula (IV) as defined above, or an optical isomer, a salt, or a
protected derivative thereof; particularly, a compound selected
from: [0229]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0230]
N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodi-
oxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;
[0231]
3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-
-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(4-fluorophenyl)benzenesulfonamide;
[0232]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-
-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(2-morpholin-4-ylethyl)benzenesulfonam-
ide; [0233]
N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-ox-
o-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0234]
4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol
idin-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0235]
2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0236]
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperazin-1-yls-
ulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one; [0237]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-N-(1-methyl-1-phenylethyl)benzenesulfonamide;
[0238]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-
-oxazolidin-3-yl]hexyl}oxy)butyl]-N-methylbenzenesulfonamide;
[0239]
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(morpholin-4-yls-
ulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one; [0240]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-N,N-dimethylbenzenesulfonamide; [0241]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-N-isopropylbenzenesulfonamide; [0242]
N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2--
oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0243]
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperidin-1-yls-
ulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one; [0244]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]phenylmethanesulfonamide; [0245]
3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]pentyl}oxy)pentyl]benzenesulfonamide; [0246]
5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-2-methoxybenzenesulfonamide; [0247]
3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]heptyl}oxy)propyl]benzenesulfonamide; [0248]
3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol
idin-3-yl]butoxy}hexyl)benzenesulfonamide; [0249]
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide; [0250]
3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)pentyl]benzenesulfonamide; [0251]
3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)hexyl]benzenesulfonamide; [0252]
3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol
idin-3-yl]hexyl}oxy)propyl]benzenesulfonamide; [0253]
3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]pentyl}oxy)butyl]benzenesulfonamide; [0254]
N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodi-
oxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;
[0255]
N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)--
2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;
[0256]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-N-[(ethylamino)carbonyl]benzenesulfonamide;
[0257]
3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide; [0258]
N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-
-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)amino]phenyl}acetamide;
[0259]
N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6--
yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;
[0260]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide;
[0261]
(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2--
oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}-N-methylethenesulfonamide;
[0262]
(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}ethenesulfonamide;
[0263] 3-[((tert-Butoxycarbonyl)
{[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-5-[4-({6-[(5R)-5-(2,2-d-
imethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl-
]-1,1'-biphenyl; [0264] tert-Butyl
{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol-
idin-3-yl]hexyl}oxy)butyl]-5-pentylphenyl}sulfonyl
{[2-(trimethylsilyl)ethoxy]methyl}carbamate; [0265]
1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide; and [0266]
1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide.
[0267] For a better understanding of the invention, the following
Examples are given by way of illustration.
SYNTHETIC EXAMPLES
[0268] Throughout the examples, the following abbreviations are
used:
LC: Liquid Chromatography
LCMS: Liquid Chromatography Mass Spectrometry.
RT: retention time
THF: tetrahydofuran
DMF: N,N-dimethylformamide
bp: boiling point
ca: circa
h: hour(s)
min: minute(s)
XRPD: X-ray powder diffraction
All temperatures are given in degrees centigrade.
Silica gel refers to Merck silica gel 60 Art number 7734.
Flash silica gel refers to Merck silica gel 60 Art number 9385.
Biotage refers to prepacked silica gel cartridges containing KP-Sil
run on flash 12i chromatography module.
Bond Elut are prepacked cartridges used in parallel purifications,
normally under vacuum. These are commercially available from
Varian.
[0269] LC was conducted on a Luna C18(2) column (5 cm.times.2.0 mm
ID) eluting with 0.05% v/v trifluoroacetic acid in water (solvent
A) and 0.05% v/v trifluoroacetic acid in acetonitrile (solvent B)
using the following elution gradient 0.00-8.00 min 0% B, 8.00-8.01
min 95% B, 8.01-10.00 min 0% B at a flow rate of 1.0 ml/min with a
column temperature of 40.degree. C.
[0270] NMR experiments at 400 MHz (unless specified otherwise).
[0271] LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3
cm.times.4.6 mm ID) eluting with 0.1% HCO.sub.2H and 0.01 M
ammonium acetate in water (solvent A), and 0.05% HCO.sub.2H 5%
water in acetonitrile (solvent B), using the following elution
gradient 0-0.7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3 min 0% B,
5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectra were
recorded on a Fisons VG Platform spectrometer using electrospray
positive and negative mode (ES+ve and ES-ve).
[0272] The XRPD analysis shown in the Figures were performed on a
Phillips X'pert Pro powder diffractometer, Model PW3040/60, serial
number DY1379. The method runs from 2 to 45 degrees 2Theta with
0.02 degree 2Theta step size and a 2 second collection time at each
step.
Example 1
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)-hexyl]oxy}butyl)benzenesulfonamide acetate
i) Di(tert-butyl)
2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate
[0273] Cesium carbonate (70.4 g) was added to a stirred suspension
of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone,
(Glaxo, DE 3513885, 1985) (61.8 g) and di-t-butyl
iminodicarboxylate (47.15 g) in acetonitrile (600 ml) under
nitrogen. After vigorous stirring at 21.degree. for 24 h the
mixture was diluted with water (ca800 ml) and the product was
extracted with diethyl ether (1 litre, then 200 ml). The combined
organic layers were washed with brine, dried (MgSO.sub.4) and
concentrated to ca400 ml. The white crystals were collected by
filtration, washed with diethyl ether and dried to give the title
compound (24.4 g) .delta. (CDCl.sub.3) 7.78(1H, dd, J 8, 2 Hz),
7.65 (1H, brs), 6.87(1H, d, J=8 Hz), 4.97(2H, s), 4.88(2H, s),
1.56(6H, s) and 1.48 (18H, s). Further concentration of the mother
liquors gave additional product (13.8 g). A third crop (7.1 g) was
obtained by chromatographing the mother liquors on silica gel,
evaporating the appropriate eluate and triturating with diethyl
ether.
ii) tert-Butyl
2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate
[0274] Trifluoroacetic acid (92 ml) was added to a stirred solution
of di(tert-butyl)
2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate,
(352.55 g) in dichloromethane (3.6 litres) at 21.degree. and the
reaction was stirred for 1.5 h. Aqueous NaOH solution (1.75 litres)
was added and after 10 min the phases were separated. The organic
layer was washed with water, dried (MgSO.sub.4) and evaporated to
an oil. This was stored under high vacuum overnight and then
triturated with hexane:ether (3:1) to give the crude product
(226.61 g). This was purified by recrystallisation from diethyl
ether to give the title compound (122.78 g). Further product (61.5
g) was obtained from the mother liquors by evaporation and
chromatography on a Biotage using 15% ethyl acetate in hexane. LCMS
RT=3.37 min.
iii) tert-Butyl
(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate
[0275] A 2M solution of borane-dimethyl sulphide in THF (28 ml) was
added slowly to a 1M solution of
(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaboro-
le in toluene (56 ml) at 0.degree. under nitrogen. A solution of
tert-butyl
2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate,
(108.2 g) in THF (1.3 litres) was added slowly keeping the
temperature below 5.degree. followed by 2M solution of
borane-dimethyl sulphide in THF (252 ml) over 50 min. After 1 h, 2M
HCl (170 ml) was added with cooling and the mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated NaHCO.sub.3 solution and brine and dried (MgSO.sub.4).
The solution was concentrated and the product purified by
chromatography on flash silica gel (800 g), eluting successively
with hexane:ethyl acetate (4:1 then 3:1) to give the title compound
(93.3 g), LCMS RT=3.31 min.
iv)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
[0276] tert-Butyl
(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,
(86.37 g) in DMF (600 ml) was added dropwise to a stirred
suspension of sodium hydride (60% oil dispersion, 11.9 g) in DMF
(160 ml) with cooling such that the internal temperature remained
at 0.degree. under nitrogen. The mixture was stirred at 21.degree.
for 2 h. The mixture was recooled to 0.degree. and 2M HCl (134 ml)
was added. The mixture was diluted with water and the product was
extracted with ethyl acetate twice. The solution was washed with
brine twice, dried (MgSO.sub.4) and evaporated to give the title
compound (63.55 g) LCMS RT=2.66 min.
v) 6-Bromohexyl but-3-ynyl ether
[0277] 3-Butyn-1-ol (42.4 ml) was stirred vigorously with
1,6-dibromohexane (260 ml) and tetrabutylammonium bisulphate (2.4
g) in 50% aqueous sodium hydroxide solution (200 ml) under nitrogen
for 3 days. Water (ca 700 ml) was added and the organic layer was
separated.
[0278] The aqueous layer was extracted twice with dichloromethane
(2.times.100 ml) and the combined organic layers were washed with
water, dried (MgSO.sub.4) and concentrated. The residue in
petroleum ether (bp 40-600) was loaded onto a column of silica gel
(1.5 kg) and the column was eluted with petroleum ether (bp
40-600), then 10% diethyl ether in petroleum ether (bp 40-600) to
give the title compound (103.3 g), .delta. (CDCl.sub.3) 3.56(2H, t,
J=7 Hz), 3.47(2H, t, J=7 Hz), 3.42(2H, t, J=7 Hz), 2.45(2H, m),
1.99(1H, t, J=2 Hz), 1.87(2H, m), 1.60(2H, m) and 1.50 to 1.33 (4H,
m).
vi)
(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-y-
l)-1,3-oxazolidin-2-one
[0279]
(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
(10 g) in DMF (100 ml) was added dropwise to a stirred suspension
of sodium hydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with
stirring under nitrogen and maintaining the internal temperature at
0.degree.. Stirring was continued at 0-5.degree. for 1 h. The
mixture was recooled to 0.degree. and a solution of 6-bromohexyl
but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over 1 min. The
mixture was then stirred at 20-30.degree. for 2 h. 2M HCl (9 ml)
was added and the mixture was partitioned between water and diethyl
ether. The aqueous layer was extracted with more diethyl ether and
the combined organic layers were washed twice with brine. After
drying (MgSO.sub.4) the solution was concentrated and loaded onto a
column of silica gel (600 g) set up in diethyl ether:petroleum
ether (bp 40-60.degree.) (1:2). The column was eluted successively
with this mixture, then (1:1) and then diethyl ether to give the
title compound (13.88 g) LCMS RT=3.45 min.
vii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0280]
(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-
-6-yl)-1,3-oxazol idin-2-one (1.79 g) was stirred with
3-iodobenzene sulphonamide (1.4 g) in acetonitrile:triethylamine
(1:1, 42 ml) under nitrogen for 10 min. Cuprous iodide (0.083 g)
and dichlorobis(triphenylphosphine)palladium (0.192 g) were added
and the mixture was stirred for 17 h under nitrogen at 210. The
mixture was evaporated to dryness and the residue was
chromatographed on silica gel (250 g) in 30% ethyl
acetate:petroleum ether (bp 40-600), then 50%, then 75% and finally
ethyl acetate to give the title compound (2.35 g), LCMS RT=3.44
min.
viii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-ox-
azolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0281]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3--
oxazol idin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide (2.35 g)
was stirred with platinum oxide (0.3 g) in THF (30 ml) under
hydrogen for 2 h. The catalyst was removed by filtration using a
filter aid and the filter cake was leached with ethyl acetate. The
combined filtrates were passed through silica gel (200 g) in ethyl
acetate and the eluate was evaporated to give the title compound
(2.32 g), LCMS RT=3.49 min.
ix)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy]butyl}benzenesulfonamide
[0282]
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3--
oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide (0.43 g) was
stirred in THF (10 ml) while purging with a vigorous stream of
nitrogen for 5 min. Potassium trimethylsilanoate (0.43 g) was added
and the mixture was stirred at 70.degree. under nitrogen for 2.5 h.
The mixture was partitioned between dichloromethane and pH 6.4
phosphate buffer and the aqueous layer was extracted with more
dichloromethane. The combined organic layers were washed with
water, dried (MgSO.sub.4) and concentrated. The residue was
purified on silica gel (60 g), eluting successively with ethyl
acetate:petroleum ether (bp 40-60.degree.) (1:1), ethyl acetate,
10% then 20% methanol in ethyl acetate to give the title compound
(0.286 g), LCMS RT=2.56 min.
[0283] x)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-
ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]a-
mino}hexyl)oxy]butyl}benzenesulfonamide (0.283 g) was stirred with
acetic acid (8 ml) and water (4 ml) at 700 for 35 min before
evaporating to dryness. The residue was re-evaporated twice with
toluene to give the title compound (0.318 g) LCMS RT=2.34 min ES+ve
495 (MH).sup.+.
Example 2
4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0284] was prepared using methods similar to those described in
Example 1 vii.
[0285] LCMS RT=3.47 min.
ii)
4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl oxy)butyl]benzenesulfonamide
[0286] was prepared using methods similar to those described in
Example 1 viii. LCMS RT=3.47 min.
iii)
4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0287] was prepared using methods similar to those described in
Example 1 ix.
[0288] LCMS RT=2.65 min.
iv)
4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)benzenesulfonamide acetate
[0289] was prepared using methods similar to those described in
Example 1 x.
[0290] LCMS RT=2.38 min, ES+ve 495 (MH).sup.+.
Example 3
2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)butyl-ynyl]benzenesulfonamide
[0291] was prepared using methods similar to those described in
Example 1 vii.
[0292] LCMS RT=3.58 min.
ii)
2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0293] was prepared using methods similar to those described in
Example 1 viii.
[0294] LCMS RT=3.61 min.
iii)
2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-benzenesulfonamide
[0295] was prepared using methods similar to those described in
Example 1 ix.
[0296] LCMS RT=2.80 min.
iv)
2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)benzenesulfonamide acetate
[0297] was prepared using methods similar to those described in
Example 1.times.
[0298] LCMS RT=2.43 min, ES+ve 495 (MH).sup.+.
Example 4
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amin-
o)hexyl]oxy}butyl)-N-methylbenzenesulfonamide acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-methylbenzenesulfonamide
[0299] was prepared using methods similar to those described in
Example 1 vii.
[0300] ES+ve 571 (MH).sup.+.
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N-methylbenzenesulfonamide
[0301] was prepared using methods similar to those described in
Example 1 viii.
[0302] ES+ve 575 (MH).sup.+.
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-N-methylbenzenesulfonamide
[0303] was prepared using methods similar to those described in
Example 1 ix.
[0304] ES+ve 549 (MH).sup.+.
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamide acetate
[0305] was prepared using methods similar to those described in
Example 1 x.
[0306] LCMS RT=2.45 min ES+ve 509 (MH).sup.+.
Example 5
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)ph-
enyl]butoxy}hexyl)amino]ethyl}phenol acetate
i)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(morpholin-4--
ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one
[0307] was prepared using methods similar to those described in
Example 1 vii.
[0308] ES+ve 627 (MH).sup.+.
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(morpholin-4--
ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one
[0309] was prepared using methods similar to those described in
Example 1 viii.
[0310] ES+ve 631 (MH).sup.+.
iii)
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(morpholin--
4-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol
[0311] was prepared using methods similar to those described in
Example 1 ix.
[0312] ES+ve 605 (MH).sup.+.
iv)
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfony-
l)phenyl]butoxy}hexyl)amino]ethyl}phenol acetate
[0313] was prepared using methods similar to those described in
Example 1x.
[0314] LCMS RT=2.54 min ES+ve 565 (MH).sup.+.
Example 6
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amin-
o)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamide acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N,N-dimethylbenzenesulfonamide
[0315] A mixture of
(5R)-3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)--
1,3-oxazolidin-2-one (0.256 g) and 3-bromo-N,N-dimethylbenzene
sulphonamide (0.208 g) in pyrrolidine (4 ml) was degassed using
vacuum/nitrogen cycle. Cuprous iodide (0.005 g) and
dichlorobis(triphenylphosphine)palladium (0.037 g) were added and
the mixture was stirred at 80.degree. for 45 min under nitrogen.
The mixture was diluted with EtOAc and washed with water. The
aqueous phase was extracted with EtOAc and the combined organic
phases washed with brine, dried (Na.sub.2SO.sub.4) and evaporated
to dryness. The residue was dissolved in CH.sub.2Cl.sub.2 and
applied to a silica Bond Elut Cartridge (10 g). The cartridge was
eluted with CH.sub.2Cl.sub.2, cyclohexane/Et.sub.2O, Et.sub.2O and
EtOAc. Evaporation of the ether fractions gave an oil which was
repurified by silica Bond Elut to give the title compound (0.23 g),
ES+ve 585 (MH).sup.+.
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N,N-dimethylbenzenesulfonamide
[0316] was prepared using methods similar to those described in
Example 1 viii.
[0317] ES+ve 587 (MH).sup.+.
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-N,N-dimethylbenzenesulfonamide
[0318] was prepared using methods similar to those described in
Example 1 ix.
[0319] ES+ve 563 (MH).sup.+.
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxmethyl)phenyl]ethyl}-a-
mino)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamide acetate
[0320] was prepared using methods similar to those described in
Example 1 x.
[0321] LCMS RT=2.52 min ES+ve 523 (MH).sup.+.
Example 7
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amin-
o)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-isopropylbenzenesulfonamide
[0322] was prepared using methods similar to those described in
Example 6 i.
[0323] ES+ve 599 (MH).sup.+.
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
ol idin-3-yl]hexyl}oxy)butyl]-N-isopropylbenzenesulfonamide
[0324] was prepared using methods similar to those described in
Example 1 viii.
[0325] ES+ve 603 (MH).sup.+.
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-N-isopropylbenzenesulfonamide
[0326] was prepared using methods similar to those described in
Example 1 ix.
[0327] ES+ve 577 (MH).sup.+.
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide acetate
[0328] was prepared using methods similar to those described in
Example 1 x.
[0329] LCMS RT=2.56 min ES+ve 537 (MH).sup.+.
Example 8
N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phe-
nyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)--
2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0330] was prepared using methods similar to those described in
Example 6i.
[0331] ES+ve 613 (MH).sup.+.
ii)
N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0332] was prepared using methods similar to those described in
Example 1 viii.
[0333] ES+ve 617 (MH).sup.+.
iii)
N-(tert-Butyl)-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-y-
l)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0334] was prepared using methods similar to those described in
Example 1 ix.
[0335] ES+ve 591 (MH).sup.+.
iv)
N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl-
)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate was
prepared
[0336] using methods similar to those described in Example 1x.
[0337] LCMS RT=2.63 min ES+ve 551 (MH).sup.+.
Example 9
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperidin-1-ylsulfonyl)ph-
enyl]butoxy}hexyl)amino]ethyl}phenol acetate
i)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(piperidin-1--
ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazol idin-2-one
[0338] was prepared using methods similar to those described in
Example 6 i.
[0339] ES+ve 625 (MH).sup.+.
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperidin-1--
ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one
[0340] was prepared using methods similar to those described in
Example 1 viii.
[0341] ES+ve 629 (MH).sup.+.
iii)
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperidin--
1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol
[0342] was prepared using methods similar to those described in
Example 1 ix.
[0343] ES+ve 603 (MH).sup.+.
iv)
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperidin-1-ylsulfony-
l)phenyl]butoxy}hexyl)amino]ethyl}phenol acetate
[0344] was prepared using methods similar to those described in
Example 1 x.
[0345] LCMS RT=2.72 min ES+ve 563 (MH).sup.+.
Example 10
1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)-hexyl]oxy}butyl)phenyl]methanesulfonamide
i) Sodium (3-iodophenyl)methanesulfonate
[0346] A solution of 3-iodobenzyl bromide (3 g) and sodium sulphite
(1.26 g) in acetone (15 ml) and water (30 ml) was heated at
70.degree. for 3 h. The solvent was removed under reduced pressure
and the residue was triturated in ether to give the title compound
(3.8 g). LCMS RT=3.66 min.
ii) (3-Iodophenyl)methanesulfonyl chloride
[0347] A stirred mixture of sodium (3-iodophenyl)methanesulfonate
(3.6 g) and phosphoryl chloride (10 ml) in sulpholane (20 ml) and
acetonitrile (30 ml) was heated at 70.degree. for 2 h. The mixture
was poured onto crushed ice (200 ml) and the precipitated product
was collected and dried to give the title product (2.8 g) LCMS
RT=3.47 min.
iii) (3-Iodophenyl)methanesulfonamide
[0348] A stirred solution of (3-iodophenyl)methanesulfonyl chloride
(1 g) in THF (20 ml) was treated with 0.88 ammonia (25 ml) at room
temperature for 30 min. The solvent was removed under reduced
pressure and the residue was triturated in ether to give the title
compound (0.35 g).
[0349] LCMS RT=2.71 min.
iv)
{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide
[0350] was prepared using methods similar to those described in
Example 1 vii.
[0351] ES+ve 571 (MH).sup.+
v)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)butyl]phenylmethanesulfonamide
[0352] was prepared using methods similar to those described in
Example 1 viii.
[0353] ES+ve 575 (MH).sup.+
vi)
{3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4-H-1,3-benzodioxin-6-yl)-2-hydroxyet-
hyl]amino}hexyl)oxy]butyl}phenyl}methanesulfonamide
[0354] was prepared using methods similar to those described in
Example 1 ix.
[0355] ES+ve 549 (MH).sup.+
vii)
[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethy-
l}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide
[0356] was prepared using methods similar to those described in
Example 1.times..
[0357] LCMS RT=2.22 min ES+ve 509 (MH).sup.+
Example 11
3-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)pentyl]oxy}pentyl)benzenesulfonamide acetate
i) 5-[(5-Bromopentyl)oxy]pent-1-yne
[0358] was prepared using methods similar to those described in
Example 1 v.
[0359] LCMS RT=3.62 min.
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[5-(pent-4-ynyloxy)pen-
tyl]-1,3-oxazolidin-2-one
[0360] was prepared using methods similar to those described in
Example 1 vi.
[0361] LCMS RT=3.50 min.
iii)
3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]pentyl}oxy)pent-1-ynyl]benzenesulfonamide
[0362] was prepared using methods similar to those described in
Example 1 vii.
[0363] LCMS RT=3.42 min.
iv)
3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]pentyl}oxy)pentyl]benzenesulfonamide
[0364] was prepared using methods similar to those described in
Example 1 viii.
[0365] LCMS RT=3.58 min.
v)
3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-
]amino}pentyl)oxy]pentyl}benzenesulfonamide
[0366] was prepared using methods similar to those described in
Example 1 ix.
[0367] LCMS RT=2.75 min.
vi)
3-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)pentyl]oxy}pentyl)benzenesulfonamide acetate
[0368] was prepared using methods similar to those described in
Example 1 x.
[0369] LCMS RT=2.46 min, ES+ve 495 (MH).sup.+.
Example 12
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)heptyl]oxy}propyl)benzenesulfonamide acetate
i) 3-[(7-Bromoheptyl)oxy]prop-1-yne
[0370] was prepared using methods similar to those described in
Example 1 v.
[0371] LCMS RT=3.63 min.
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[7-(prop-2-ynyloxy)hep-
tl]-1,3-oxazolidin-2-one
[0372] was prepared using methods similar to those described in
Example 1 vi.
[0373] LCMS RT=3.57 min.
iii)
3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]heptyl}oxy)prop-1-ynyl]benzenesulfonamide
[0374] was prepared using methods similar to those described in
Example 1 vii.
[0375] LCMS RT=3.51 min.
iv)
3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]heptyl}oxy)propyl]benzenesulfonamide
[0376] was prepared using methods similar to those described in
Example 1 viii.
[0377] LCMS RT=3.58 min.
v)
3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-
]amino}heptyl)oxy]propyl}benzenesulfonamide
[0378] was prepared using methods similar to those described in
Example 1 ix.
[0379] LCMS RT=2.75 min.
vi)
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)heptyl]oxy}propyl)benzenesulfonamide acetate
[0380] was prepared using methods similar to those described in
Example 1 x.
[0381] LCMS RT=2.46 min, ES+ve 495 (MH).sup.+.
Example 13
3-{6-[4-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-
butoxy]hexyl}benzenesulfonamide acetate
i) 6-(4-Bromobutoxy)hex-1-yne
[0382] was prepared using methods similar to those described in
Example 1 v.
[0383] LCMS RT=3.49 min.
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[4-(hex-5-ynyloxy)buty-
l]-1,3-oxazolidin-2-one
[0384] was prepared using methods similar to those described in
Example 1 vi.
[0385] LCMS RT=3.48 min.
iii)
3-(6-{-4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]butoxy}hex-1-ynyl)benzenesulfonamide
[0386] was prepared using methods similar to those described in
Example 1 vii.
[0387] LCMS RT=3.42 min.
iv)
3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]butoxy}hexyl)benzenesulfonamide
[0388] was prepared using methods similar to those described in
Example 1 viii.
[0389] LCMS RT=3.58 min.
v)
3-[6-(4-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-
amino}butoxy)hexyl]benzenesulfonamide
[0390] was prepared using methods similar to those described in
Example 1 ix.
[0391] LCMS RT=2.66 min.
vi)
3-{6-[4-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)butoxy]hexyl}benzenesulfonamide acetate
[0392] was prepared using methods similar to those described in
Example 1 x.
[0393] LCMS RT=2.47 min, ES+ve 495 (MH).sup.+.
Example 14
4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamide
i) 4-(3-Iodophenyl)butyl methanesulfonate
[0394] 4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with
diisopropylamine (1.74 ml) and methanesulfonyl chloride (0.66 ml)
in dichloromethane (50 ml) at 21.degree. for 2 h. The solution was
washed successively with sodium bicarbonate solution, water, water
acidified with a few drops of 2M HCl and water, each time back
extracting with dichloromethane. The combined organic layers were
dried (MgSO.sub.4) and evaporated to give the title compound (2,23
g), tlc R.sub.f=0.28 (1:3 ethyl acetate in cyclohexane)
ii) 4-(3-Iodophenyl)butane-1-sulfonamide
[0395] 4-(3-Iodophenyl)butyl methanesulfonate (0.354 g) was stirred
with sodium iodide (0.75 g) in acetone (5 ml) under nitrogen for 3
h and at 350 for 30 min. The mixture was partitioned between
dichloromethane and water. The aqueous layer was extracted with
more dichloromethane and the combined organic layers were washed
with water. After drying (MgSO.sub.4) the solution was evaporated
to an oil. This was dissolved in ethanol (10 ml) and water (5 ml)
and the mixture was refluxed on a steam bath for 12 h with sodium
sulfite (0.138 g). The mixture was cooled and the solid was
collected by filtration, washed with water and dried. This residue
was refluxed with phosphorus oxychloride (4 ml) under nitrogen for
4 h and then blown dry with a stream of nitrogen. 0.880 Ammonia
solution (5 ml) was added and the mixture was refluxed for 2 h.
More ammonia solution (5 ml) was added and refluxing was continued
for 45 min. The mixture was cooled and the solid was collected by
filtration, washed with water and dried to give the title compound
(0.2 g) LCMS RT=3.15 min.
iii)
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3--
oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}butane-1-sulfonamide
[0396] was prepared using methods similar to those described in
Example 1 vii.
[0397] LCMS RT=3.62 min.
iv)
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-o-
xazolidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide
[0398] was prepared using methods similar to those described in
Example 1 viii.
[0399] LCMS RT=3.71 min.
v)
4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl-
}amino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamide
[0400]
4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1-
,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide
(0.097 g) was stirred and refluxed with potassium
trimethylsilanoate (0.1 g) under nitrogen for 2 h. The mixture was
evaporated to dryness and re-evaporated with methanol. The residue
was taken up in methanol and loaded onto a Bond Elut SCX2 cartridge
(10 g) which had been preconditioned with methanol. The cartridge
was left for 30 min and then eluted successively with methanol and
then 1% 0.880 aqueous ammonia solution in methanol. This gave the
title compound (0.064 g), LCMS RT=2.72 min, ES+ve 551
(MH).sup.+.
Example 15
3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}pentyl)benzenesulfonamide
i) 5-[(6-bromohexyl)oxy]pent-1-yne
[0401] was prepared using methods similar to those described in
Example 1 v.
[0402] GCMS RT=5.6 min
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(pent-4-ynyloxy)hex-
yl]-1,3-oxazol idin-2-one
[0403] was prepared using methods similar to those described in
Example 1 iv.
[0404] LCMS RT=3.65 min
iii)
3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zol idin-3-yl]hexyl}oxy)pent-1-ynyl]benzenesulfonamide
[0405] was prepared using methods similar to those described in
Example 1 vii.
[0406] LCMS RT=3.76 min
iv)
3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)pentyl]benzenesulfonamide
[0407] was prepared using methods similar to those described in
Example 1 viii.
[0408] LCMS RT=3.57 min
v)
3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}pentyl)benzenesulfonamide
[0409] was prepared using methods similar to those described in
Example 14 v.
[0410] LCMS R=2.47 min, ES+ve 509 (MH).sup.+.
Example 16
3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}hexyl)benzenesulfonamide
i) 6-[(6-Bromohexyl)oxy]hex-1-yne
[0411] was prepared using methods similar to those described in
Example 1 v.
[0412] GCMS RT=5.99 min
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(hex-5-ynyloxy)hexy-
l]-1,3-oxazolidin-2-one
[0413] was prepared using methods similar to those described in
Example 1 iv.
[0414] LCMS RT=3.73 min
iii)
3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)hex-1-ynyl]benzenesulfonamide
[0415] was prepared using methods similar to those described in
Example 1 vii.
[0416] LCMS RT=3.74 min
iv)
3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)hexyl]benzenesulfonamide
[0417] was prepared using methods similar to those described in
Example 1 viii.
[0418] LCMS RT=3.69 min
v)
3-(6-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}hexyl)benzenesulfonamide
[0419] was prepared using methods similar to those described in
Example 14 v.
[0420] LCMS RT=2.57 min, ES+ve 523 (MH).sup.+.
Example 17
3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}propyl)benzenesulfonamide acetate
i) 3-[(6-Bromohexyl)oxy]prop-1-yne
[0421] was prepared using methods similar to those described in
Example 1 v. .delta. (CDCl.sub.3) 4.13 (2H, s), 3.52 (2H, t, J=7
Hz), 3.41 (2H, t, J=7 Hz), 2.42 (1H, t J 2 Hz), 1.91 to 1.82 (2H,
m), 1.66 to 1.58 (2H, m) and 1.51 to 1.35 (4H, m).
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(prop-2-ynyloxy)hex-
yl]-1,3-oxazolidin-2-one
[0422] was prepared using methods similar to those described in
Example 1 vi.
[0423] LCMS RT=3.45 min
iii)
3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)prop-1-ynyl]benzenesulfonamide
[0424] was prepared using methods similar to those described in
Example 1 vii.
[0425] LCMS RT=3.52 min
iv)
3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)propyl]benzenesulfonamide
[0426] was prepared using methods similar to those described in
Example 1 viii.
[0427] LCMS RT=3.48 min
v)
3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-
]amino}hexyl)oxy]propyl}benzenesulfonamide
[0428] was prepared using methods similar to those described in
Example 1 ix.
[0429] LCMS RT=2.81 min
vi)
3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}propyl)benzenesulfonamide acetate
[0430] was prepared using methods similar to those described in
Example 1 x.
[0431] LCMS RT=2.48 min, ES+ve481 (MH).sup.+.
Example 18
3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)pentyl]oxy}butyl)benzenesulfonamide acetate
i) 4-[(5-Bromopentyl)oxy]but-1-yne
[0432] was prepared using methods similar to those described in
Example 1 v.
[0433] .delta. (MeOD) 3.43 (2H, t, J=7 Hz), 3.41 to 3.32 (4H, m),
2.32 (2H, dt, J 2,7 Hz), 2.15 (1H, t, J=2 Hz), 1.81 to 1.73 (2H,
m), 1.54 to 1.38 (4H, m).
ii)
(5R)-3-[5-(But-3-ynyloxy)pentyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6--
yl)-1,3-oxazol idin-2-one
[0434] was prepared using methods similar to those described in
Example 1 vi.
[0435] LCMS RT=3.87 min
iii)
3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]pentyl}oxy)but-1-ynyl]benzenesulfonamide
[0436] was prepared using methods similar to those described in
Example 1 vii.
[0437] LCMS RT=3.47 min
iv)
3-[4-(5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]pentyl}oxy)butyl]benzenesulfonamide
[0438] aas prepared using methods similar to those described in
Example 1 viii.
[0439] LCMS RT=3.37 min
v)
3-{4-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-
]amino}pentyl)oxy]butyl}benzenesulfonamide
[0440] was prepared using methods similar to those described in
Example 1 ix.
[0441] LCMS RT=2.81 min
vi)
3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)pentyl]oxy}butyl)benzenesulfonamide acetate
[0442] was prepared using methods similar to those described in
Example 1 x.
[0443] LCMS RT=2.41 min, ES+ve 481 (MH).sup.+.
Example 19
N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydr-
oxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
acetate
N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodi-
oxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonami-
de
[0444] was prepared using methods similar to those described in
Example 1 vii.
[0445] LCMS RT=3.72 min.
i)
N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzo-
dioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0446] was prepared using methods similar to those described in
Example 1 viii.
[0447] LCMS RT=3.61 min.
ii)
N-[3-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-ben-
zodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0448] was prepared using methods similar to those described in
Example 1 ix.
[0449] LCMS RT=2.88 min.
iii)
N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3--
(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
acetate
[0450] was prepared using methods similar to those described in
Example 1 x.
[0451] LCMS RT=2.95 min, ES+ve 650 (MH).sup.+.
Example 20
1-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)phenyl]methanesulfonamide
i) Sodium (4-iodophenyl)methanesulfonate
[0452] was prepared using methods similar to those described in
Example 10 i.
[0453] tlc (SiO.sub.2, 1:1 EtOAc/Cyclohexane/1% AcOH)Rf=0.57).
ii) 1-(4-Iodophenyl)methanesulfonamide
[0454] was prepared using methods similar to those described in
Example 10 iii.
[0455] LCMS RT=2.63 min
iii)
1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3--
oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide
[0456] was prepared using methods similar to those described in
Example 1 vii.
[0457] LCMS RT=3.43 min
iv)
1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-o-
xazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide
[0458] was prepared using methods similar to those described in
Example 1 viii.
[0459] LCMS RT=3.50 min
v)
1-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl-
}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide
[0460] was prepared using methods similar to those described in
Example 14 v.
[0461] LCMS RT=2.35, ES+ve 509 (MH).sup.+.
Example 21
1-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)phenyl]methanesulfonamide
i) Sodium (2-iodophenyl)methanesulfonate
[0462] was prepared using methods similar to those described in
Example 10 i.
[0463] tlc (SiO.sub.2, 1:1 EtOAc/Cyclohexane/1% AcOH)Rf=0.63.
ii) 1-(2-Iodophenyl)methanesulfonamide
[0464] was prepared using methods similar to those described in
Example 10 iii.
[0465] LCMS RT=2.44 min
iii)
1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3--
oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide
[0466] was prepared using methods similar to those described in
Example 1 vii.
[0467] LCMS RT=3.46 min
iv)
1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-o-
xazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide
[0468] was prepared using methods similar to those described in
Example 1 viii.
[0469] LCMS RT=3.50 min
v)
1-[2-(4-({[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethy-
l}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide
[0470] was prepared using methods similar to those described in
Example 14 v.
[0471] LCMS RT=2.40, ES+ve 509 (MH).sup.+.
Example 22
N-Benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]et-
hyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo--
1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0472] was prepared using methods similar to those described in
Example 6 i. ES+ve 647 (MH).sup.+
ii)
N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-
-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0473] was prepared using methods similar to those described in
Example 1 viii. ES+ve 651 (MH).sup.+
iii)
N-Benzyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-3-benzodioxin-6-yl)-2-hyd-
roxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0474] was prepared using methods similar to those described in
Example 1 ix. ES+ve 625 (MH).sup.+
iv) N-benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
[0475] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.72 min, ES+ve 585 (MH).sup.+
Example 23
4-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]butoxy}h-
exyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzene
acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)butyl]-N-[(ethylamino)carbonyl]benzenesulfonamide
[0476] Ethyl isocyanate (0.015 g) was added to a stirred mixture of
3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazoli-
din-3-yl]hexyl}oxy)butyl]benzenesulfonamide (0.11 g) and
K.sub.2CO.sub.3 (0.055 g) in acetone (2 ml). The mixture was heated
at reflux for 2 h then ethyl isocyanate (0.005 g) was added. After
0.5 h the reaction mixture was cooled and quenched with water (1
ml). The mixture was partitioned between EtOAc (20 ml) and H.sub.2O
(20 ml). The aqueous phase was extracted with EtOAc (20 ml). The
combined EtOAc phases were washed with brine (10 ml) then dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
SPE (silica 5 g) with
[0477] CH.sub.2Cl.sub.2 (2.times.15 ml), Et.sub.2O (2.times.15 ml)
and EtOAc (2.times.15 ml), evaporation of the EtOAc fractions
afforded the title compound (0.067 g). ES+ve 632 (MH).sup.+
ii)
4-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]buto-
xy}hexyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzene
acetate
[0478] was prepared using methods similar to those described in
Example 1.times.. LCMS RT=2.86 min, ES+ve 606 (MH).sup.+
Example 24
3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexy-
l]oxy}butyl)benzenesulfonamide acetate
i) tert-Butyl
2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate
[0479] Recrystallisation of a batch of 3:1 (R:S) Example 1 iii
(78.94 g) gave the title compound (27.6 g).
[0480] LCMS RT=3.31 min
ii)
5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
[0481] was prepared using methods similar to those described in
Example 1 iv. ES+ve 250 (MH).sup.+
iii)
3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1-
,3-oxazolidin-2-one
[0482] was prepared using methods similar to those described in
Example 1 vi. ES+ve 402 (MH).sup.+
iv)
3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidi-
n-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0483] was prepared using methods similar to those described in
Example 1 vii. ES+ve 557 (MH).sup.+
v)
3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-
-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0484] was prepared using methods similar to those described in
Example 1 viii. ES+ve 561 (MH).sup.+
vi)
3-{4-[(6-{[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]ami-
no}hexyl)oxy]butyl}benzenesulfonamide
[0485] was prepared using methods similar to those described in
Example 1 ix. ES+ve 535 (MH).sup.+
vii)
3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)benzenesulfonamide acetate
[0486] was prepared using methods similar to those described in
Example 1.times.. LCMS RT=2.90 min, ES+ve 495 (MH).sup.+
Example 25
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
3-{-4-[(6-{[(2S)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy]butyl}benzenesulfonamide
[0487] Resolution of
3-{4-[(6-{[2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}-
hexyl)oxy]butyl}benzenesulfonamide (0.403 g) on an HPLC Chiralcel
OJ column using 40% ethanol/heptane afforded the title compound
(0.096 g).
ii)
3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)benzenesulfonamide acetate
[0488] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.44 min, ES+ve 495 (MH).sup.+
Example 26
N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]eth-
yl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamide
acetate
i)
N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1-
,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}sulfonyl)amino]phenyl}aceta-
mide was prepared using methods similar to those described in
Example 1 vii. ES-ve 688 (M-H).sup.-
ii)
N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo--
1,3-oxazol
idin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)amino]phenyl}acetamid-
e
[0489] was prepared using methods similar to those described in
Example 1 viii. ES-ve 692 (M-H).sup.-
iii)
N-(4-{[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hy-
droxyethyl]amino}hexyl)oxyl
butyl}phenyl)sulfonyl]amino}phenyl)acetamide
[0490] was prepared using methods similar to those described in
Example 1 ix. ES+ve 668 (MH).sup.+
iv)
N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl-
]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamide
acetate GW671337A R5965/48/11
[0491] was prepared using methods similar to those described in
Example 1.times.. LCMS RT=2.59 min, ES+ve 628 (MH).sup.+
Example 27
N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)pheny-
l]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
(i)
N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0492] was prepared using methods similar to those described in
Example 1 vii. ES+ve 611 (MH).sup.+
ii)
N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-oxo-1,3-oxazol idin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0493] was prepared using methods similar to those described in
Example 1 viii. ES+ve 615 (MH).sup.+
iii)
N-Cyclobutyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0494] was prepared using methods similar to those described in
Example 1 ix. ES+ve 589 (MH).sup.+
iv)
N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)p-
henyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
[0495] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.72 min, ES+ve 549 (MH).sup.+
Example 28
N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)pheny-
l]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2--
oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide
[0496] was prepared using methods similar to those described in
Example 1 vii. ES+ve 639 (MH).sup.+
ii)
N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-
-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0497] was prepared using methods similar to those described in
Example 1 viii. ES+ve 643 (MH).sup.+
iii)
N-Cyclohexyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0498] was prepared using methods similar to those described in
Example 1 ix. ES+ve 617 (MH).sup.+
iv)
N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)p-
henyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
[0499] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.85 min, ES+ve 577 (MH).sup.+
Example 29
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide
acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(2-morpholin-4-ylethyl)benzenesulfonami-
de
[0500] was prepared using methods similar to those described in
Example 1 vii. ES+ve 670 (MH).sup.+
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl]-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N-(2-morpholin-4-ylethyl)benzenesulfonamide
[0501] was prepared using methods similar to those described in
Example 1 viii. ES+ve 674 (MH).sup.+
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]-amino}hexyl)oxy]butyl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide
[0502] was prepared using methods similar to those described in
Example 1 ix. ES+ve 648 (MH).sup.+
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide
acetate
[0503] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.22 min, ES+ve 608 (MH).sup.+
Example 30
N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd-
roxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfon-
amide
[0504] was prepared using methods similar to those described in
Example 6 i. ES+ve 645 (MH).sup.+
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamid-
e
[0505] was prepared using methods similar to those described in
Example 1 viii. ES+ve 647 (MH).sup.-
iii)
N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-
-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
[0506] was prepared using methods similar to those described in
Example 14 v. LCMS RT=2.62 min, ES+ve 583 (MH).sup.+
Example 31
N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl-
)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(4-fluorophenyl)benzenesulfonamide
[0507] was prepared using methods similar to those described in
Example 1 vii. ES+ve 651 (MH).sup.+
ii)
3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N-(4-fluorophenyl)benzenesulfonamide
[0508] was prepared using methods similar to those described in
Example 1 viii. ES+ve 655 (MH).sup.+
iii)
3-{-4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyet-
hyl]amino}hexyl)oxy]butyl}-N-(4-fluorophenyl)benzenesulfonamide
[0509] was prepared using methods similar to those described in
Example 1 ix. ES+ve 629 (MH).sup.+
iv)
N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxyme-
thyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
acetate
[0510] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.81 min, ES+ve 589 (MH).sup.+
Example 32
N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydr-
oxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
acetate
i)
N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzo-
dioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfona-
mide
[0511] was prepared using methods similar to those described in
Example 1 vii. ES+ve 712 (MH).sup.+
ii)
N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benz-
odioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide
[0512] was prepared using methods similar to those described in
Example 1 viii. ES+ve 716 (MH).sup.+
iii)
N-[4-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-be-
nzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0513] was prepared using methods similar to those described in
Example 1 ix. ES+ve 690 (MH).sup.+
iv)
N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(-
hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
acetate
[0514] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.61 min, ES+ve 650 (MH).sup.+
Example 33
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{-4-[3-(piperazin-1-ylsulfonyl)p-
henyl]butoxy}hexyl)amino]ethyl}phenol acetate
i)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(piperazin-1--
ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one
[0515] was prepared using methods similar to those described in
Example 1 vii. ES+ve 626 (MH).sup.+
ii)
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperazin-1--
ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one
[0516] was prepared using methods similar to those described in
Example 1 viii. ES+ve 630 (MH).sup.+
iii)
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperazin--
1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol
[0517] was prepared using methods similar to those described in
Example 1 ix. ES+ve 604 (MH).sup.+
iv)
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-14-[3-(piperazin-1-ylsulfony-
l)phenyl]butoxy}hexyl)amino]ethyl}phenol acetate
[0518] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.23 min, ES+ve 564 (MH).sup.+
Example 34
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamide
acetate
i)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(1-methyl-1-phenylethyl)benzenesulfonam-
ide
[0519] was prepared using methods similar to those described in
Example 1 vii. ES-ve 673 (M-H).sup.-
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-N-(1-methyl-1-phenylethyl)benzenesulfonamide
[0520] was prepared using methods similar to those described in
Example 1 viii. ES-ve 677 (M-H).sup.-
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]-amino}hexyl)oxy]butyl}-N-(1-methyl-1-phenylethyl)benzenesulfonamide
[0521] was prepared using methods similar to those described in
Example 1 ix. ES+ve 653 (MH).sup.+
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamide
acetate
[0522] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.90 min, ES+ve 613 (MH).sup.+
Example 35
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amin-
o)hexyl]oxy}butyl)-2-methoxybenzenesulfonamide acetate
i)
5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazo-
lidin-3-yl]hexyl}oxy)but-1-ynyl]-2-methoxybenzenesulfonamide
[0523] was prepared using methods similar to those described in
Example 1 vii. ES+ve 587 (MH).sup.+
ii)
5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-2-methoxybenzenesulfonamide
[0524] was prepared using methods similar to those described in
Example 1 viii. ES+ve 591 (MH).sup.+
iii)
5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-2-methoxybenzenesulfonamide
[0525] was prepared using methods similar to those described in
Example 1 ix. ES+ve 565 (MH).sup.+
iv)
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)-2-methoxybenzenesulfonamide acetate
[0526] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.41 min, ES+ve 525 (MH).sup.+
Example 36
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethy-
l}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide
i) 4-(3-Bromophenyl)but-3-yn-1-ol
[0527] A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g)
and 3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine
(100 ml) was purged with nitrogen for 20 min under nitrogen.
Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous
iodide (800 mg) were added. The mixture was stirred for 18 h and
then the solvent was removed in-vacuo. The residual oil was
triturated with ethyl acetate (200 ml) and filtered. The filtrate
was evaporated to dryness and the residue was purified by
chromatography on Biotage (90 g) eluting with light petroleum
40-60.degree.-diethyl ether (3:2) to give the title compound (21
g). LCMS RT=3.26 min.
ii) 4-(3-Bromophenyl)butan-1-ol
[0528] A solution of 4-(3-bromophenyl)but-3-yn-1-ol (21 g) in
ethanol (1000 ml) was hydrogenated over platinum oxide (500 mg) for
4 h. The catalyst was removed by filtration and the filtrate was
evaporated to give the title compound (18 g) tlc (SiO.sub.2)
diethyl ether Rf=0.38.
iii) 1-Bromo-3-{4-[(6-bromohexyl)oxy]butyl}benzene
[0529] A stirred mixture of 4-(3-bromophenyl)butan-1-ol (18 g) and
1,6 dibromohexane (48 ml) in 50% aq. sodium hydroxide (500 ml) with
tetrabutylammonium bromide (1.5 g) was stirred for 2d at
20.degree.. The mixture was poured into water (1000 ml) and
extracted into ethyl acetate (3.times.500 ml). The combined
extracts were washed with water (1000 ml), dried
(Na.sub.2SO.sub.4). The solvent was removed in-vacuo and the
residual oil was purified by flash chromatography (500 g) using
dichloromethane as eluent, changing to light petroleum
(40-60.degree.)-diethyl ether (9:1) to give the title compound (18
g). LCMS RT=4.34 min.
iv)
(5R)-3-{6-[4-(3-Bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzo-
dioxin-6-yl)-1,3-oxazolidin-2-one
[0530] Sodium hydride (60% dispersion in oil, 690 mg) was added to
a stirred solution of
5R-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-1,3-oxazolidin-2-one (3.0
g) in dry DMF (35 ml) at 5.degree. C. under nitrogen. After 20 min
a solution of 1-bromo-3-{4-[(6-bromohexyl)oxy]butyl}benzene (5.64
g) in dry DMF (15 ml) was added. The mixture was stirred at ambient
temperature for 4 h. The mixture was poured into an ammonium
chloride solution (300 ml) and extracted into ethyl acetate
(3.times.100 ml). The combined extracts were washed with water (200
ml), dried (Na.sub.2SO.sub.4) and evaporated. The residual oil was
purified by chromatography on Biotage (90 g) eluting with diethyl
ether-light petroleum (bp 40-60) (4:1) to give the title compound
(5.2 g). LCMS RT=4.13 min.
v)
(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,-
3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}-N-methylethenesulfonamide
[0531] A stirred mixture
(5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodio-
xin-6-yl)-1,3-oxazolidin-2-one (1.0 g), N-methylethenesulphonamide
(WO 95/09166), (462 mg), tri-o-tolylphosphine (200 mg), palladium
acetate (165 mg) and triethylamine (5 ml) in dry DMF (15 ml) was
heated at 90.degree. C. for 18 h. The mixture was cooled and
filtered. The filtrate was poured into water (200 ml) and extracted
into ethyl acetate (3.times.50 ml). The combined extracts were
washed with water (100 ml) and (Na.sub.2SO.sub.4) and evaporated in
vacuo. The residual oil was purified by chromatography on Biotage
(40 g) eluting with diethyl ether-ethyl acetate (9:1) to give the
title compound (220 mg). LCMS RT=3.70 min.
vi)
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydr-
oxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide
[0532] Was prepared using methods similar to those described in
Example 1ix.
[0533] LCMS RT=2.96 min
vii)
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl-
]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide
[0534] A solution of
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-
ethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide (100
mg) in methanol (15 ml) was administered onto a Bond Elut SCX2
cartridge (10 g), which had been preconditioned in methanol. The
cartridge was eluted with methanol (2.times.25 ml) followed by 15%
aq. ammonia-methanol (2.times.20 ml). Evaporation of the latter
fractions gave the title compound (70 mg) LCMS RT=2.59 min, ES+ve
535 (MH)+
viii)
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)pheny-
l]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethanesulfonamide
compound with (2E)-but-2-enedioic acid (1:1)
[0535] A solution of
(E)-2-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]eth-
yl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide (60 mg)
and fumaric acid (6.5 mg) in ethanol was evaporated to dryness to
give the title compound (66 mg) LCMS RT=2.65 min, ES+ve 537
(MH).sup.+
Example 37
2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)phenyl]ethanesulfonamide
i) tert-Butyl vinylsulfonylcarbamate
[0536] Di-tert-butyldicarbonate (8.62 g) was added to a stirred,
cooled (ice bath) solution of ethenesulphonamide (S. Hirooka, Bull.
Chem. Soc. Jpn. 1991, 64, 1431) (3.4 g), 4-(dimethylamino)pyridine
(410 mg) and triethylamine (7 ml) in dichloromethane (40 ml) under
nitrogen. The solution was stirred for 30 min, washed with 2M
hydrochloric acid (30 ml), water (50 ml) and dried
(Na.sub.2SO.sub.4) to give the title compound (5.0 g). Tlc
(SiO.sub.2, 1:1 diethyl ether-cyclohexane) Rf=0.4.
ii)
(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1-
,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}ethenesulfonamide
[0537] Was prepared using methods similar to those described in
Example 36 v. LCMS RT=3.6 min
iii)
(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hyd-
roxyethyl]amino}hexyl)oxy]butyl}phenyl)ethenesulfonamide
[0538] Was prepared using methods similar to those described in
Example 1 ix.
[0539] LCMS RT=2.87 min
iv)
(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-
ethyl}amino)hexyl]oxy}butyl)phenyl]ethenesulfonamide
[0540] Was prepared using methods similar to those described in
Example 1 x.
[0541] LCMS RT=2.55 min
v)
2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl-
}amino)hexyl]oxy}butyl)phenyl]ethanesulfonamide
[0542] Was prepared using methods similar to those described in
Example 1 viii.
[0543] LCMS RT=2.73 min, ES+ve 523 (MH).sup.+
Example 38
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)[1,1'-biphenyl]-3-sulfonamide acetate
i) tert-Butyl (3,5-diiodophenyl)sulfonylcarbamate
[0544] Di tert-butyl dicarbonate (1.11 g) was added to a stirred
solution of 3,5 di-iodo-benzenesulfonamide (Tsatsas, Chem. Chron.
1974, 3, 143) (1.6 g), 4-(dimethylamino)pyridine (50 mg) and
triethylamine (0.8 ml) in dichloromethane (30 ml) at 5.degree.. The
solution was stirred at ambient temperature for 1 h, washed with 1M
hydrochloric acid (30 ml), water (50 ml) and dried
(Na.sub.2SO.sub.4). The solvent was evaporated to give the title
compound (1.6 g). LCMS RT=4.24 min.
ii) tert-Butyl
(3,5-diiodophenyl)sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate
[0545] Sodium hydride (60% dispersion in oil, 157 mg) was added to
a stirred solution of tert-butyl
(3,5-diiodophenyl)sulfonylcarbamate (1.6 g) in DMF (10 ml) at
5.degree. under nitrogen. After 10 min
2-(trimethylsilyl)ethoxymethyl chloride (0.61 ml) was added. The
mixture was stirred for 30 min. The reaction mixture was poured
into aq. ammonium chloride (100 ml) and extracted into diethyl
ether (3.times.40 ml). The organic extracts were washed with water
(30 ml), dried (Na.sub.2SO.sub.4) and evaporated to give the title
compound (1.95 g). LCMS RT=4.47 min.
iii) tert-Butyl
{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol-
idin-3-yl]hexyl}oxy)but-1-ynyl]-5-iodophenyl}sulfonyl{[2-(trimethylsilyl)e-
thoxy]methyl}carbamate
[0546] A solution of (5R)
3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-o-
xazolidin-2-one (233 mg) and tert-butyl
(3,5-diiodophenyl)sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate
(410 mg) in dry acetonitrile (3 ml) and triethylamine (3 ml) was
purged with nitrogen for 30 min. Cuprous iodide (50 mg) and
dichlorobis(triphenylphosphine)palladium (50 mg) were then added.
The mixture was stirred for 18 h at ambient temperature and then
evaporated to dryness. The residual oil was purified by
chromatography on Biotage (8 g) eluting with diethyl
ether-petroleum ether (bp 40-60.degree.). The appropriate fractions
were evaporated to give the title compound (190 mg). LCMS RT=4.54
min.
iv)
3-[((tert-Butoxycarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfo-
nyl]-5-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)but-1-ynyl]-1,1'-biphenyl
[0547] A stirred mixture of tert-butyl
{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol-
idin-3-yl]hexyl}oxy)but-1-ynyl]-5-iodophenyl}sulfonyl
{[2-(trimethylsilyl)ethoxy]methyl}carbamate (190 mg),
benzeneboronic acid (62 mg) in dimethoxyethane (4 ml) and 1M sodium
carbonate (2 ml) with tetrakis(triphenylphosphine)palladium(0) (25
mg) was heated at 800 for 1 h. The mixture was poured into water
(20 ml) and extracted into ethyl acetate (3.times.30 ml). The
organic extracts were dried (Na.sub.2SO.sub.4) and evaporated. The
residual oil was purified by chromatography on Biotage (8 g)
eluting with cyclohexane-diethyl ether (4:1) to give the title
compound (140 mg). LCMS RT=4.54 min.
v)
3-[((tert-Butoxycarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfon-
yl]-5-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)butyl]-1,1'-biphenyl
[0548] was prepared using methods similar to those described in
Example 1 viii.
[0549] LCMS RT=4.55 min.
vi)
5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy}butyl)[1,1'-biphenyl]-3-sulfonamide
[0550] Was prepared using methods similar to those described in
Example 1 ix. LCMS RT=2.86 min.
vii)
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-
amino)hexyl]oxy}butyl)[1,1'-biphenyl]-3-sulfonamide acetate
[0551] Was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.76 min, ES+ve 571(MH).sup.+.
Example 39
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amin-
o)hexyl]oxy}butyl)-5-pentylbenzenesulfonamide acetate
i) tert-Butyl
{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol-
idin-3-yl]hexyl}oxy)but-1-ynyl]-5-pent-1-ynylphenyl}sulfonyl
{[2-(trimethylsilyl)ethoxy]methyl}carbamate
[0552] Was prepared using methods similar to those described in
Example 1 vii. LCMS RT=4.77 min.
ii) tert-Butyl
{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazol-
idin-3-yl]hexyl}oxy)butyl]-5-pentylphenyl}sulfonyl{[2-(trimethylsilyl)etho-
xy]methyl}carbamate
[0553] Was prepared using methods similar to those described in
Example 1 viii. LCMS RT=4.7 min.
iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyeth-
yl]amino}hexyl)oxy]butyl}-5-pentylbenzenesulfonamide
[0554] Was prepared using methods similar to those described in
Example 1 ix. LCMS RT=3.21 min.
iv)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}--
amino)hexyl]oxy}butyl)-5-pentylbenzenesulfonamide acetate
[0555] Was prepared using methods similar to those described in
Example 1 x
[0556] LCMS RT=2.93 min, ES+ve 565 (MH).sup.+
Example 40
3-(4-{[6-({(2R)-2Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}aminoh-
exyl]oxy}butyl)benzenesulfonamide
(i) 6-(But-3-ynyloxy)hexanal
[0557] 6-Bromohexylbut-3-ynyl ether (DE3513885A1) (525 mg) in DMSO
(2 ml) was added to a mixture of sodium bicarbonate (1 g) in DMSO
(8 ml) at 150.degree. C. with vigorous stirring and nitrogen
bubbling through the solution. The mixture was stirred for 20 min
at 150.degree. C. and then allowed to cool to room temperature,
diluted with diethyl ether and washed with water. The aqueous layer
was extracted with diethyl ether and the combined ether layers were
washed with dilute hydrochloric acid, brine, dried (MgSO.sub.4) and
evaporated to dryness to give the title compound (325 mg): IR 1726
cm.sup.-1 MS(TSP+ve) m/z 186 (M+MH.sub.4).sup.+.
(ii)
(1R)-2-{[6-(But-3-ynyloxy)hexyl][(1S)-2-hydroxy-1-phenylethyl]amino}--
1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
[0558] A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and
(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenyl-
ethyl]amino}ethanol (710 mg) (WO/0196278) in chloroform (10 ml) was
treated at 20.degree. C. with sodium triacetoxyborohydride (866 mg)
and stirred under nitrogen for 2 days. The mixture was diluted with
ethyl acetate and aqueous sodium bicarbonate solution. The organic
phase was separated and washed with sodium bicarbonate solution,
brine, dried and purified on a silica Bond Elut cartridge (10 g)
eluting with dichloromethane, diethyl ether and finally ethyl
acetate to give the title compound (810 mg): LCMS RT=2.69 min,
ES+ve m/z 496 (M+H).sup.+.
(iii)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyet-
hyl][(1S)-2-hydroxy-1-phenylethyl]amino}hexyl)oxy]but-1-ynyl}benzenesulfon-
amide
[0559] was prepared using methods similar to those described in
Example 1 vii.
[0560] LCMS RT=2.85 min
(iv)
3-(4-{[6-({(2R)-2Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
minohexyl]oxy}butyl)benzenesulfonamide
[0561]
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-
ethyl][(1S)-2-hydroxy-1-phenylethyl]amino}hexyl)oxy]but-1-ynyl}benzenesulf-
onamide (104 mg) was hydrogenated in ethanol (50 ml) over
Pearlman's catalyst (60 mg) over 4 h and then over 10% Pd/C (100
mg) over 4 days. The catalyst was removed by filtration and washed
with ethanol. The filtrate was concentrated and then applied to an
SCX-2 cartridge eluting with methanol, followed by 0.67M ammonia in
methanol. The ammonia fractions were concentrated and purified by
chromatography on Biotage (4 g cartridge) eluting with
dichloromethane-methanol-2M ammonia in methanol (50:8: 1) to give
the title compound (11 mg) LCMS RT=2.34 min ES+ve 495
(M+H).sup.+.
Example 41
3-Fluoro-5-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]et-
hyl}amino)hexyl]oxy}butyl)benzenesulfonamide
i) 3-Fluoro-5-iodobenzenesulfonamide
[0562] 3-Fluoro-5-iodoaniline (3.06 g) (WO 9623783) was added to a
stirred mixture of concentrated hydrochloric acid (4 ml) and water
(4 ml). Glacial acetic acid (8 ml) was added and the reaction
mixture cooled to -5.degree. C. A solution of sodium nitrite (0.99
g) in water (8 ml) was added dropwise maintaining the temperature
between -5.degree. C. and -2.degree. C. After the addition was
complete the reaction was stirred for 10 min. In the meantime
glacial acetic acid (20 ml) was saturated with sulfur dioxide gas
for 0.25 h, then copper(I) chloride (0.353 g) was added. Additional
sulfur dioxide was bubbled through the solution until a fine
suspension was obtained. The mixture was cooled to 5.degree. C. and
then treated portionwise with the diazonium salt prepared above.
After stirring at room temperature for 1 h ice (50 g) was added.
The mixture was extracted with ether (100 ml) and the organic
phases washed with NaHCO.sub.3 solution (2.times.100 ml) then water
(100 ml), dried (MgSO.sub.4) and concentrated. The residue was
dissolved in THF (30 ml) at 0.degree. C. and aqueous ammonia
(0.880; 5 ml) was added. After stirring at room temperature the
mixture was partitioned between EtOAc (100 ml) and water (100 ml).
The organic phase was washed with brine (50 ml), dried (MgSO.sub.4)
and concentrated. The residue was purified by chromatography using
cyclohexane-EtOAc (5:1 then 3:1). Evaporation of the fractions and
trituration of the residue with cyclohexane afforded the title
compound (0.886 g). ES-ve 299 (M-H).sup.-
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)but-1-ynyl]-5-fluorobenzenesulfonamide
[0563] was prepared using methods similar to those described in
Example 1 vii. ES+ve 575 (MH).sup.+
iii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)butyl]-5-fluorobenzenesulfonamide
[0564] was prepared using methods similar to those described in
Example 1 viii. ES+ve 579 (MH).sup.+
iv)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy]butyl}-5-fluorobenzenesulfonamide
[0565] was prepared using methods similar to those described in
Example 1 ix. ES+ve 553 (MH).sup.+
v)
3-Fluoro-5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl-
]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
[0566] was prepared using methods similar to those described in
Example 36 vii. LCMS RT=2.50 min, ES+ve 513 (MH).sup.+
Example 42
5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)-3-trifluoromethylbenzenesulfonamide
i) 3-Bromo-5-trifluoromethylbenzenesulfonamide
[0567] was prepared using methods similar to those described in
Example i. ES-ve 302,304 (M-H).sup.-
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)but-1-ynyl]-5-(trifluoromethyl)benzenesulfonamide
[0568] was prepared using methods similar to those described in
Example 6 i. ES+ve 625 (MH).sup.+
iii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)butyl]-5-trifluoromethylbenzenesulfonamide
[0569] was prepared using methods similar to those described in
Example 1 viii. ES+ve 629 (MH).sup.+
iv)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy]butyl}-5-(trifluoromethyl)benzenesulfonamide
[0570] was prepared using methods similar to those described in
Example 1 ix. ES+ve 603 (MH).sup.+
v)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)-5-(trifluoromethyl)benzenesulfonamide
[0571] was prepared using methods similar to those described in
Example 36 vii. LCMS RT=2.57 min, ES+ve 563 (MH).sup.+
Example 43
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)-5-methylbenzenesulfonamide acetate
i) 3-Bromo-5-methylbenzenesulfonamide
[0572] was prepared from 3-bromo-5-methylaniline (EP303387A1) using
methods similar to those described in Example 41(i). LCMS RT=2.80
min
ii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxaz-
olidin-3-yl]hexyl}oxy)but-1-ynyl]-5-methylbenzenesulfonamide
[0573] was prepared using methods similar to those described in
Example 1 vii. LCMS RT=3.54 min
iii)
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxa-
zolidin-3-yl]hexyl}oxy)butyl]-5-methylbenzenesulfonamide
[0574] was prepared using methods similar to those described in
Example 1 viii. LCMS RT=3.60 min
iv)
3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethy-
l]amino}hexyl)oxy]butyl}-5-methylbenzenesulfonamide
[0575] was prepared using methods similar to those described in
Example 1 ix. LCMS RT=2.73 min
v)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}am-
ino)hexyl]oxy}butyl)-5-methylbenzenesulfonamide
[0576] was prepared using methods similar to those described in
Example 1 x. LCMS RT=2.43 min, ES+ve 509 (MH.sup.+)
Example 44
N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)phenyl]sulfonyl}glycine acetate
N.sup.2-[(3-Iodophenyl)sulfonyl]glycinamide
[0577] (3-Iodophenyl)sulphonyl chloride (0.303 g) was stirred with
glycinamide hydrochloride (0.122 g) and diisopropylethylamine (0.3
ml) in DMF (4 ml) at 21.degree. for 24 h. The mixture was
evaporated to dryness and applied to a silica Bond Elut Cartridge
(10 g). The cartridge was eluted with CH.sub.2Cl.sub.2, Et.sub.2O
and EtOAc. This gave the title compound (0.146 g), LCMS RT=2.36
min, ES+ve 341 (MH).sup.+
ii)
N.sup.2-({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-ox-
o-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}sulfonyl)glycinamide
[0578] was prepared using methods similar to those in Example 1 vii
LCMS RT=3.26 min, ES+ve 614 (MH).sup.+
iii)
N.sup.2-({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-o-
xo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)glycinamide
[0579] was prepared using methods similar to those in Example 1
viii LCMS RT=3.23 min, ES+ve 618 (MH).sup.+
iv)
N-[(3-{-4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydrox-
yethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]glycine
[0580] was prepared using methods similar to those in Example 1 ix
LCMS RT=2.70 min, ES+ve 593 (MH).sup.+
v) N--F
[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]et-
hyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl]glycine acetate
[0581] was prepared using methods similar to those in Example 1 x
LCMS RT=2.38 min, ES+ve 553 (MH).sup.+
Example 45
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)hexyl]oxy}butyl)benzenesulfonamide
(i) 6-Bromohexyl but-3-ynyl ether
[0582] A mixture of 50% w/v aqueous sodium hydroxide (2500 ml),
1,6-dibromohexane (2610 g) and tetra-butylammonium bromide (25 g)
was warmed to 50.degree. C., with stirring. But-3-yn-1-ol (500 g)
was then added to the reaction mixture at such a rate as to ensure
the content's temperature did not exceed 65.degree. C. The reaction
was left at 50.degree. C. overnight before being cooled to room
temperature. Tert-butyl methyl ether (2500 ml) and brine (2000 ml)
was added to the cooled mixture and the layers allowed to separate.
The ethereal layer was washed with water (2.times.2000 ml), brine
(1.times.2000 ml), and then dried over anhydrous MgSO.sub.4. The
solution was filtered and concentrated under reduced pressure to
give crude product as a liquid. This was further purified by
fractional distillation using a 60 cm vacuum jacketed Vigreux
column at ca. 0.5 mbar. The product was obtained in the fraction
which boiled at 92-98.degree. C., to give the title compound (518
g), LC RT=6.16, .delta. (CDCl.sub.3) 3.55 (2H, t, J=6.9 Hz), 3.46
(2H, t, J=6.9 Hz), 3.41 (2H, t, J=6.9 Hz), 2.46 (2H, dt, J 2.5, 6.9
Hz), 1.98 (1H, t, J=2.5 Hz), 1.86 (2H, m), 1.59 (2H, m), 1.46 (2H,
m), 1.38 (2H, m).
(ii) 3-{-4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide
[0583] A mixture of 3-bromo-benzenesulfonamide (625 g),
6-bromohexyl but-3-ynyl ether (850.1 g),
bis(triphenylphosphine)palladium (II) chloride (62.5 g),
triphenylphosphine (18.1 g) and triethylamine (536.3 g) in
tetrahydrofuran (6250 ml) was stirred under an atmosphere of
nitrogen for 20 mins. Copper (I) iodide (12.5 g) was then added to
give a dark red/brown mixture that was heated to 50.degree. C. for
23 h. The reaction mixture was then cooled to room temperature and
filtered through a short silica pad (100 g). The pad was washed
with additional tetrahydrofuran (15.6 L) and the resulting solution
then concentrated under reduced pressure to give crude product
(1382 g) as a viscous oil. This was purified by chromatography (7
kg silica) eluting with 5:1 petroleum ether:ethyl acetate followed
by 2:1 petroleum ether:ethyl acetate to give the title compound
(932.9 g) as an oil, LC RT=5.69 min, .delta. (DMSO-d.sub.6) 7.79
(1H, s), 7.76 (1H, d, J=7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55
(2H, t, J=6.6 Hz), 3.49 (2H, t, J=6.6 Hz), 3.42 (2H, t, J=6.6 Hz),
2.68 (2H, t, J=6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H,
m).
(iii) 3-{4-[(6-Bromohexyl)oxy]butyl}benzenesulfonamide
[0584] 3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide (627
g) in IMS (1900 ml) was stirred with activated charcoal (314 g) at
room temperature for 2 h and then filtered through a short pad of
Celite. The filter pad was washed with IMS (4300 ml) and the
filtrate transferred to a hydrogenation vessel. 5% Platinum on
Charcoal (520.1 g, .about.50% water) was added and the reaction
mixture was then stirred under an atmosphere of hydrogen (0.2 bar)
at 20.degree. C. for 6 h. The mixture was then filtered through a
short pad of Celite and concentrated under reduced pressure to give
the title compound (499 g) as a solid, LC RT=5.66, .delta.
(DMSO-d.sub.6) 7.65 (1H, s), 7.64 (1H, d, J=9.2 Hz), 7.47 (1H, m),
7.42 (1H, m), 7.31 (2H, s), 3.50 (2H, t, J=6.9 Hz), 3.34 (4H, m),
2.66 (2H, t, J=7.5 Hz), 1.78 (2H, m), 1.62 (2H, m), 1.49 (4H, m),
1.37 (2H, m), 1.30 (2H, m).
(iv) (1R)
2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
[0585] A solution R-diphenylprolinol (75 mg) in THF (2 ml) was
treated with borane-THF (1M, 20.5 ml) over 20 min at 20.degree. C.
under nitrogen. After the addition was complete the solution was
kept between 30 and 35.degree. C. for 1 h and then cooled in ice
and 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone
(DE3513885) (3.9 g) in THF (10 ml) was added over 1.5 h keeping the
temperature below 5.degree. C. The mixture was stirred under
nitrogen for a further 0.5 h and then methanol (4 ml) was added at
0.degree. C. The solvent was removed under reduced pressure and the
residue was purified by chromatography on flash silica gel eluting
with ethyl acetate-cyclohexane (1:4) to give the title compound
(3.31 g) o (CDCl.sub.3) 7.15 (1H, dd, J 8, 2 Hz), 7.03 (1H, br s),
6.82 (1H, d, J=8 Hz), 4.85 (3H, sand m), 3.61 (1H, dd, J 10,4 Hz),
3.50 (1H, dd, J 10, 9 Hz), 1.54 (6H, s).
(v)
{[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(trie-
thyl)silane
[0586] Triethylsilyl chloride (205 g) was added dropwise to a
stirred mixture of
(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350
g) and imidazole (108.5 g) in DMF (875 ml) at 5.degree. C. Upon
complete addition the mixture was warmed to 15.degree. C. and
stirred, at this temperature for 1 h. N-hexane (3500 ml) was then
added to the mixture which was washed with water (3.times.750 ml).
The organic layer was dried over anhydrous MgSO.sub.4 before being
filtered and concentrated under reduced pressure to give the title
compound (488.6 g) as an oil, LC RT=7.97 min, 6 (DMSO-d.sub.6) 7.18
(1H, d, J=8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J=8.2 Hz), 4.83 (1H,
m), 4.78 (2H, d, J=6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H,
t, J=8.1 Hz), 0.51 (6H, m).
(vi)
N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethy-
lsilyl)oxy]ethyl}amine
[0587] A mixture of
{[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethy-
l)silane (130 g) and benzylamine (177 ml) in 1,4-dioxane (650 ml)
was heated at 105.degree. C. with stirring overnight. The mixture
was then cooled to room temperature and water (150 ml) and diethyl
ether (1200 ml) added. The layers were separated and the ethereal
layer was washed with saturated ammonium chloride solution
(3.times.600 ml), saturated sodium bicarbonate solution (200 ml)
and then brine (200 ml). The solution was dried over anhydrous
Na.sub.2SO.sub.4 before being filtered and concentrated under
reduced pressure to give the title compound (129.9 g) as an oil, LC
RT=5.20 min, .delta. (CDCl.sub.3) 7.22 (5H, m), 7.02 (1H, d, J=8.7
Hz), 6.86 (1H, s), 6.68 (1H, d, J=8.3 Hz), 4.75 (2H, s), 4.69 (1H,
m), 3.73 (2H, s), 2.70 (2H, m), 1.46 (6H, s), 0.79 (9H, m), 0.44
(6H, m).
(vii)
(1R)-2-(Benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
[0588] Tetrabutylammonium fluoride (395 ml, 1M in THF) was added
dropwise to a stirred solution of
N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsil-
yl)oxy]ethyl}amine (129.9 g) in THF (900 ml) at 5.degree. C. Upon
complete addition the reaction mixture was maintained at this
temperature for 15 min before water (600 ml) was added. The
resulting slurry was diluted with diethyl ether (500 ml) and
filtered. The filtrate was washed with water (2.times.500 ml) and
brine (500 ml) before being dried over anhydrous Na.sub.2SO.sub.4.
The resulting mixture was filtered and concentrated under reduced
pressure to give a solid which was triturated with diisopropyl
ether to give the title compound (70 g) as a solid, LC RT=3.34 min,
.delta. (CDCl.sub.3) 7.31 (5H, m), 7.09 (1H, d, J=8 Hz), 6.98 (1H,
s), 6.77 (1H, d J 8 Hz), 4.82 (2H, s), 4.63 (1H, m), 3.83 (2H, d,
J=4 Hz), 2.80 (2H, m), 1.52 (6H, s).
(viii)
3-{4-[(6-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hy-
droxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide
[0589] A stirred mixture of
3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (11.1 g),
(1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
(9 g) and diisopropyl ethylamine (8.9 ml) in acetonitrile (28 ml)
was heated at reflux for 18 h. The resulting mixture was cooled to
room temperature, diluted with diethyl ether (250 ml) and washed
with water (2.times.100 ml) and brine (100 ml) before being dried
over anhydrous Na.sub.2SO.sub.4. The suspension was filtered and
concentrated under reduced pressure to give the title compound (20
g) as an oil. LC RT=4.68 min, .delta. (CDCl.sub.3) 7.70 (2H, m),
7.38 (2H, m), 7.29 (5H, m), 7.02 (1H, d, J=8.3 Hz), 6.91 (1H, s),
6.73 (1H, d, J=8.3 Hz), 4.79 (2H, s), 4.53 (1H, m), 3.87 (1H, m),
3.40 (5H, m), 2.69 (2H, t, J=7.2 Hz), 2.54 (2H, m), 2.43 (2H, m),
1.70 (2H, m), 1.60 (2H, m), 1.51 (10H, m), 1.25 (4H, m)
(ix)
3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-
ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide
[0590] Hydrochloric acid (80 ml, 1M) was added dropwise to a
stirred solution of
3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxye-
thyl]amino}hexyl)oxy]butyl}benzenesulfonamide (20 g) in ethanol
(100 ml) at 0.degree. C. Upon complete addition the mixture was
stirred at 5.degree. C. for 1 h before being allowed to warm to
room temperature. A portion (50 ml) of the ethanol was removed
under reduced pressure and the remaining mixture was diluted with
ethyl acetate (250 ml). The mixture was then washed with water (100
ml), saturated sodium bicarbonate solution (100 ml) and brine (100
ml) before being dried over anhydrous Na.sub.2SO.sub.4. The
suspension was filtered and concentrated under reduced pressure to
give the title compound (16 g) as an oil. LC R=4.02 min, .delta.
(DMSO-d.sub.6) 9.15 (1H, s), 7.65 (1H, s), 7.64 (1H, d, J=8.8 Hz),
7.45 (2H, m), 7.27 (8H, m), 6.94 (1H, dd, J=8.2 Hz), 6.67 (1H, d,
J=8.2 Hz), 4.92 (1H, t, J=5.7 Hz), 4.67 (1H, s), 4.56 (1H, m), 4.45
(2H, d, J=5.7 Hz), 3.61 (2H, m), 3.34 (2H, t, J=6.3 Hz), 3.28 (2H,
t, J=6.2 Hz), 2.66 (2H, m), 2.50 (2H, m), 2.39 (2H, m), 1.61 (2H,
m), 1.50 (2H, m), 1.39 (4H, m), 1.16 (4H, m).
(x)
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)hexyl]oxy}butyl)benzenesulfonamide
[0591] 5% Pd/C (8 g, 50% wet) was added to a solution of
3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethy-
l}amino)hexyl]oxy}butyl)benzenesulfonamide (16 g) in IMS and the
mixture was stirred under hydrogen for 6 h. The resulting
suspension was filtered through a plug of Celite which was then
washed with IMS (160 ml). The combined washings were concentrated
under reduced pressure to give the title compound (12.8 g) as an
oil, LC RT=3.51 min, .delta. (CD.sub.3OD) 7.64 (1H, s), 7.61 (1H,
m), 7.33 (2H, m), 7.20 (1H, s), 7.01 (1H, dd, J 2.2, 8.2 Hz), 6.65
(1H, d, J=8.2 Hz), 4.61 (1H, m), 4.54 (2H, s), 3.33 (4H, m), 2.72
(2H, m) 2.63 (2H, m), 2.57 (2H, m) 1.62 (2H, m), 1.46 (6H, m), 1.27
(4H, m).
Example 46
[0592] The following salts of the compound of Example 45 were
prepared as described below.
(i) Cinnamate Salt
[0593] Cinnamic acid (0.3 g) was added to a solution of
3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amin-
o)hexyl]oxy}butyl)benzenesulfonamide (1.0 g) in methanol (5 ml) at
room temperature. The solution was stirred for 5 minutes before
being concentrated under reduced pressure to give a pale yellow
gum. Water (10 ml) was added to the gum and the reulting suspension
stirred at room temperature for 24 h. The suspension was then
filtered to give the title compound as a white solid (0.72 g),
which was then recrystallised from ethanol (SmI) to give a white
solid (0.54 g) mp 127-128.degree. C., .delta. (CD.sub.3OD) 7.73
(1H, s), 7.71 (1H, d, J=7.5 Hz), 7.50 (2H, d, J=7 Hz), 7.41 (3H,
m), 7.32 (4H, m), 7.16 (1H, dd, J 2.2, 8.2 Hz), 6.78 (1H, d, J=8.2
Hz), 6.49 (1H, d, J=16.4 Hz), 4.88 (1H, dd, J 3.8, 9.5 Hz), 4.65
(2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.69 (2H, t,
J=7.5 Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).
(ii) 1-Hydoxynaphthoate Salt
[0594] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 60-69.degree. C., .delta. (CD.sub.3OD) 8.28 (1H, d, J=8.2
Hz), 7.85 (1H, d, J=8.8 Hz), 7.72 (3H, m), 7.48 (1H, m), 7.39 (4H,
m), 7.19 (1H, d, J=8.8 Hz), 7.16 (1H, d, J=8.2 Hz), 6.78 (1H, d,
J=8.2 Hz), 4.88 (1H, m), 4.65 (2H, s), 3.35 (4H, m), 3.10 (2H, m)
2.99 (2H, m), 2.66 (2H, t, J=7.5 Hz) 1.65 (4H, m), 1.51 (4H, m),
1.34 (4H, m).
(iii) 4-Phenylbenzoate Salt
[0595] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 134-136.degree. C., .delta. (CD.sub.3OD) 8.01 (2H, d,
J=8.1 Hz), 7.73 (1H, s), 7.70 (1H, d, J=6.9 Hz), 7.62 (4H, m), 7.43
(4H, m), 7.34 (2H, m), 7.16 (1H, dd, J 2.6, 8.1 Hz), 6.78 (1H, d,
J=8.1 Hz), 4.86 (1H, m), 4.64 (2H, s), 3.42 (4H, m), 3.08 (2H, m)
2.98 (2H, t, J=7.5 Hz), 2.71 (2H, t, J=7.5 Hz) 1.70 (4H, m), 1.57
(4H, m), 1.40 (4H, m).
(iv) Triphenylacetate Salt
[0596] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 99-102.degree. C., .delta. (CD.sub.3OD) 7.74 (1H, s), 7.70
(1H, d, J 6.2 Hz), 7.42 (2H, m), 7.32 (1H, s), 7.27 (6H, m), 7.19
(6H, m), 7.13 (4H, m), 6.77 (1H, d, J=8.2 Hz), 4.85 (1H, dd, J 4.4,
9.4 Hz), 4.65 (2H, s), 3.42 (4H, m), 3.04 (2H, m) 2.94 (2H, t,
J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz) 1.70 (4H, m), 1.57 (4H, m), 1.40
(4H, m).
(v) 4-Methyl Cinnamate Salt
[0597] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 110-113.degree. C., .delta. (CD.sub.3OD) 7.73 (1H, s),
7.71 (1H, d, J=7.5 Hz), 7.39 (6H, m), 7.16 (3H, m), 6.78 (1H, d,
J=8.2 Hz), 6.45 (1H, d, J=15.7 Hz), 4.88 (1H, dd, J 3.8, 10.0 Hz),
4.65 (2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.68 (2H, t,
J=7.5 Hz) 2.31 (3H, s), 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H,
m).
(vi) 4-Methoxy Cinnamate salt
[0598] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 115-118.degree. C., .delta. (CD.sub.3OD) 7.73 (1H, s),
7.71 (1H, d, J=6.9 Hz), 7.40 (5H, m), 7.35 (1H, s), 7.16 (1H, d,
J=8.2 Hz), 6.89 (2H, d, J=8.8 Hz) 6.78 (1H, d, J 8.8 Hz), 6.37 (1H,
d, J=16.4 Hz), 4.88 (1H, dd, J 3.2, 10.0 Hz), 4.65 (2H, s), 3.78
(3H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.68 (2H, t,
J=7.5 Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).
(vii) 3-(2-Naphthalenyl)-2-propanoate Salt
[0599] Was prepared using methods similar to those quoted above,
isolation from methanol/water gave the title compound as a white
solid mp 139-144.degree. C., .delta. (CD.sub.3OD) 7.91 (1H, s),
7.83 (3H, m), 7.72 (3H, m), 7.59 (1H, d, J=15.7 Hz), 7.47 (2H, m),
7.41 (2H, m), 7.34 (1H, s), 7.16 (1H, dd, J 2.5, 8.1 Hz), 6.78 (1H,
d, J=8.1 Hz), 6.62 (1H, d, J=16.4 Hz), 4.85 (1H, m), 4.65 (2H, s),
3.40 (4H, m), 3.08 (2H, m) 2.98 (2H, m), 2.70 (2H, t, J=7.5 Hz)
1.69 (4H, m), 1.56 (4H, m), 1.39 (4H, m).
Example 47
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)heptyl]oxy}propyl)benzenesulfonamide
(i) 7-Bromoheptyl prop-2-ynyl ether
[0600] 25% (w/w) aq. NaOH (700 ml) was added to a stirred mixture
of propargyl alcohol (70 g), tetra-butyl ammonium bromide (3.5 g)
and 1,7-dibromoheptane (322 g) maintaining the temperature below
30.degree. C. The reaction mixture was heated at 60.degree. C. for
5 hrs then allowed to cool to room temperature and stirred
overnight. Diethyl ether (350 ml) and water (280 ml) were added,
the mixture stirred and allowed to settle. The aqueous layer was
extracted with diethyl ether (210 ml), the organic layers combined,
dried (MgSO.sub.4). The solution was concentrated to give 280 g of
crude material. 140 g Of the crude was purified by chromatography
on Biotage (800 g) eluting with petroleum ether then petroleum
ether:ethyl acetate (100:1 followed by 100:1.5) to give the title
compound (49.6 g).
[0601] NMR-300 MHz-.delta. (CDCl.sub.3)-4.05 (2H, d, J=2 Hz), 3.45
(2H, t, J=6.5 Hz), 3.35 (2H, t, J=7 Hz), 2.35 (1H, s), 1.8 (2H, m),
1.5 (2H, m), 1.3 (4H, m).
(ii) 3-{3-[(7-Bromoheptyl)oxy]prop-1-ynyl}benzenesulfonamide
[0602] 7-Bromoheptyl prop-2-ynyl ether (55.1 g) in THF (250 ml) was
added dropwise over ca 8 h to a stirred mixture of
3-bromobenzenesulfonamide (43.5 g), PdCl.sub.2(PPh.sub.3).sub.2
(6.48 g), PPh.sub.3 (1.45 g), CuI (1.4 g) and Et.sub.3N (52 ml) in
THF (250 ml) at 55.+-.5.degree. C. under nitrogen then the mixture
heated for a further ca 15 hrs. The reaction was cooled, filtered
through Celite and the solids washed with THF. The solution was
concentrated and the product purified by chromatography on flash
silica gel (600 g) eluting with petroleum ether:ethyl acetate
(ratios ranging successively from 19:1 to 7:3) to give the title
compound (33 g)-LC RT=5.85 min.
[0603] NMR-300 MHz-.delta. (CDCl.sub.3)-7.95 (1H, t, J=1.5 Hz),
7.78 (1H, dt, J 8, 2 Hz), 7.55 (1H, dt, J 7.75, 2 Hz), 7.40 (1H, t,
J=8 Hz), 5.0 (2H, br s), 4.3 (2H, s), 3.4 (2H, t, J=6.5 Hz), 3.35
(2H, t, J=7.25 Hz), 1.75 (2H, m), 1.55 (2H, m), 1.3 (4H, m).
(iii) 3-{3-[(7-Bromoheptyl)oxy]propyl}benzenesulfonamide
[0604] 3-{3-[(7-Bromoheptyl)oxy]prop-1-ynyl}benzenesulfonamide
(29.4 g) was dissolved in Industrial Methylated Spirits (IMS) (300
ml). Nuchar charcoal (15 g, 50% w/w) was added and the suspension
stirred at room temperature for ca 1.5 h. After filtering off the
charcoal and washing the filtrate with IMS (60 ml) the solution was
then treated in two separate lots: 5% Pd/C catalyst (11.25 g, 50%
wet) was added to each, the mixtures hydrogenated at atmospheric
pressure and temperature for ca 1-2 h, the catalyst filtered off,
rinsed with IMS (ca 10 ml) and the filtrate concentrated to give
the crude product as a solid which was recrystallised from
diisopropyl ether (100 ml) to give the title compound as a solid
(15.1 g)-LC RT=5.91 min.
[0605] NMR-300 MHz-.delta. (CDCl.sub.3)-7.75 (2H, m), 7.45 (2H, m),
4.9 (2H, br s), 3.42 (6H, m), 2.8 (2H, t, J=7.5 Hz), 1.9 (4H, m),
1.65-1.55 (4H, m), 1.5-1.3 (4H, m).
(iv) 3-{3-[(7-{Benzyl
[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hepty-
l)oxy]propyl}benzenesulfonamide
[0606] A mixture of
(1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
(55.8 g), 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (63.65
g), N,N-diisopropylethylamine (55 ml) and acetonitrile (200 ml) was
stirred and heated under N.sub.2 at reflux for ca 21 h. The mixture
was cooled to room temperature then diethyl ether (1000 ml) and
water (500 ml) were added and the mixture stirred. The organic
phase was washed with water (500 ml), then saturated brine (500 ml)
and dried (Na.sub.2SO.sub.4). The solution was concentrated and the
product purified by chromatography on flash silica gel (1000 g),
eluting with petroleum ether:ethyl acetate (ratios ranging
successively from 4:1 to 1:1) to give the title compound (97.7
g)-LC RT=1.54 min. 6 (DMSO-d.sub.6)-7.75 (2H, m), 7.45 (1H, t, J=8
Hz), 7.4 (1H, m), 7.35 (2H, s), 7.25 (5H, m), 7.05 (1H, d, J=8.5
Hz), 7.0 (1H, s), 6.7 (1H, d, J=8.5 Hz), 4.9 (1H, br s), 4.78 (2H,
s), 4.6 (1H, m), 3.65 (1H, d, J=13.8 Hz), 3.55 (1H, d, J=13.8 Hz),
3.4 (1H, br s), 3.3 (4H, m), 2.7 (2H, m), 2.55 (2H, m), 2.4 (2H,
m), 1.85 (2H, m), 1.45 (8H, m), 1.35 (2H, m), 1.25 (2H, m), 1.15
(4H, m).
(v)
3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]e-
thyl}amino)heptyl]oxy}propyl)benzenesulfonamide
[0607] To a stirred, ice-cooled solution of
3-{3-[(7-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxye-
thyl]amino}heptyl)oxy]propyl}benzenesulfonamide (97.2 g) in IMS
(417 ml) was gradually added aqueous 1M hydrochloric acid (417 ml)
keeping the temperature below 15.degree. C. The mixture was then
stirred at room temperature for ca 5 h. Saturated sodium
bicarbonate (417 ml) and ethyl acetate (1000 ml) were then added to
the mixture. The organic layer was separated off, washed with water
(400 ml), brine (400 ml) and finally dried (Na.sub.2SO.sub.4).
Concentration in vacuo gave the title compound (87.9 g)-LC RT=4.01
min.
[0608] .delta. (CDCl.sub.3)-7.75 (1H, br s), 7.70 (1H, m), 7.4-7.25
(8H, m), 7.0 (1H, d, J=8 Hz), 6.95 (1H, s), 6.75 (1H, d, J=8 Hz),
4.7 (2H, s), 4.55 (1H, m), 3.9 (1H, d, J=13 Hz), 3.55 (1H, d, J=13
Hz), 3.4 (4H, m), 2.75 (2H, t, J=7.5 Hz), 2.65 (1H, m), 2.55 (2H,
d, J=7 Hz), 2.45 (1H, m), 1.87 (2H, m), 1.55 (4H, m), 1.3 (6H,
m).
(vi)
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-
amino)heptyl]oxy}propyl)benzenesulfonamide
[0609]
3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phen-
yl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (87.2 g) in
methanol (800 ml) was hydrogenated over 5% Pd/C catalyst (28 g, 50%
wet) at atmospheric pressure and ambient temperature. The catalyst
was removed by filtration through a Hyflo pad and the filtrate
concentrated in vacuo to give the title compound (64.4 g)-LC
RT=3.46 min.
[0610] .delta. (DMSO-d.sub.6)-7.65 (2H, m), 7.45 (2H, m), 7.25 (1H,
s), 6.95 (1H, dd, J 8, 2 Hz), 6.67 (1H, d, J=8 Hz), 5.0 (2H, br
m,), 4.45 (3H, m), 3.35 (4H, m), 3.15 (2H, m), 2.7 (2H, m),
2.55-2.45 (4H, m), 1.8 (2H, m), 1.5 (2H, m), 1.35 (2H, m), 1.25
(6H, m).
Example 48
(i)
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}a-
mino)heptyl]oxy}propyl)benzenesulfonamide(E)-3-(napthalen-2-yl)-2-propenoa-
te
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino-
)heptyl]oxy}propyl)benzenesulfonamide
[0611] (1 g) was taken up in ethanol (6 ml) at room temperature
with stirring and (E)-3-(napthalen-2-yl)-2-propenoic acid (0.39 g)
added. The mixture was heated to ca 60.degree. C. until a solution
formed. The solution was cooled to room temperature and seed
crystals of the title compound added. The mixture was aged for 65
h, the product filtered, washed with ethanol (1 ml) and dried to
give the title compound (1.05 g) M Pt.=135.degree. C.-146.degree.
C.
[0612] .delta. (MeOH-d.sub.4) 7.95 (1H, s), 7.87 (3H, m), 7.75 (3H,
m), 7.60 (1H, d, J=16 Hz), 7.45 (5H, m), 7.40 (1H, m), 6.8 (1H, d,
J=8 Hz), 6.65 (1H, d, J=16 Hz), 4.9 (1H, m), 4.65 (2H, s), 3.4 (4H,
m), 3.12 (2H, m), 3.05 (2H, br t, J=8 Hz), 2.75 (2H, t, J=8 Hz),
1.87 (2H, m), 1.72 (2H, m), 1.56 (2H, m), 1.40 (6H, m).
Alternatively:
[0613]
3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]eth-
yl}amino)heptyl]oxy}propyl)benzenesulfonamide (0.5 g), dissolved in
methanol (10 ml) was treated with
(E)-3-(napthalen-2-yl)-2-propenoic acid (0.194 g). The clear
solution was evaporated to dryness and re-dissolved in ethanol (3
ml) and heated to reflux. The solution was allowed to cool to room
temperature and after 48 h the product filtered, washed with
ethanol (2 ml) and dried to give the title compound (0.58 g), M Pt
135-146.degree. C.
(ii) 4-Phenylbenzoate Salt
[0614] In a similar fashion to the previous example, the title salt
was prepared (0.5 g). The XRPD pattern of this product is shown in
FIG. 1. .delta. (MeOH-d.sub.4) 8.05 (2H, d, J=8 Hz), 7.75 (2H, m),
7.65 (4H, m), 7.45 (4H, m), 7.35 (2H, m), 7.17 (1H, d, J=8 Hz), 6.8
(1H, d, J=8 Hz), 4.9 (s), 4.65 (2H, s), 3.42 (4H, m), 3.12 (2H, m),
3.02 (2H, m), 2.80 (2H, t, J=8 Hz), 1.90 (2H, m), 1.72 (2H, m),
1.55 (2H, m), 1.40 (2H, br s).
(iii) Triphenylacetate Salt
[0615] In a similar fashion, the title salt was prepared (0.485 g).
The XRPD pattern of this product is shown in FIG. 2.
[0616] .delta. (MeOH-d.sub.4) 7.86 (2H, m), 7.58 (2H, m), 7.48 (1H,
m), 7.42 (6H, m), 7.35 (6H, m), 7.27 (4H, m), 6.92 (1H, d, J=8 Hz),
5.00 (m), 4.78 (2H, s), 3.55 (4H, m), 3.50 (1H, s), 3.20 (2H, m),
3.10 (2H, m), 2.92 (2H, m), 2.05 (2H, m), 1.80 (2H, m), 1.72 (2H,
m), 1.5 (6H, m).
(iv) 4-Phenylcinnamate Salt
[0617] In a similar fashion the title salt was prepared (0.243 g).
The XRPD pattern of this product is shown in FIG. 3. .delta.
(MeOH-d.sub.4) 7.7 (2H, m), 7.55 (6H, m), 7.35 (5H, m), 7.29 (2H,
m), 7.1 (1H, d, J=8 Hz), 6.75 (1H, d, J=8 Hz), 6.56 (1H, d, J=15.5
Hz), 4.85 (m), 4.60 (2H, s), 3.35 (4H, m), 3.05 (2H, m), 2.95 (2H,
m), 2.7 (2H, t, J=8 Hz), 1.8 (2H, m), 1.65 (2H, m), 1.5 (2H, m),
1.3 (6H, br s).
(v) Sulphamate Salt
[0618] In a similar fashion the title salt was prepared (0.56 g).
The XRPD pattern of this product is shown in FIG. 4.
(vi) Sulphanilate Salt
[0619] In a similar fashion, the title salt was prepared (0.52 g).
The XRPD pattern of this product is shown in FIG. 5. M Pt
117.degree. C.-123.degree. C.
[0620] .delta. (MeOH-d.sub.4) 7.65 (1H, s), 7.62 (1H, d, J=7 Hz),
7.45 (2H, m), 7.35 (2H, m), 7.25 (1H, s), 7.05 (1H, d, J=7 Hz), 6.7
(1H, d, J=8 Hz), 6.55 (2H, d, J=8 Hz), 4.9 (m), 4.55 (2H, s), 3.33
(4H, m), 3.05 (2H, m), 2.95 (2H, t, J=8 Hz), 2.65 (2H, t, J=8 Hz),
1.8 (2H, m), 1.6 (2H, m), 1.48 (2H, m), 1.3 (6H, br s)
Example 49
N.sup.2-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]e-
thyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamide acetate
i)
N.sup.2-[(3-Iodophenyl)sulfonyl]-N.sup.2-{[2-(trimethylsilyl)ethoxy]met-
hyl}glycinamide
[0621] N.sup.2-[(3-Iodophenyl)sulfonyl]glycinamide (0.14 g) was
stirred with sodium hydride (60% oil dispersion, 0.02 g) in DMF (2
ml) at 21.degree. under nitrogen for 15 min.
2-Trimethylsilylethoxymethyl chloride (0.08 ml) was added and
stirring was continued for 1.5 h. The mixture was poured into pH
6.4 phosphate buffer and the product was extracted three times with
ethyl acetate. The combined organic layers were washed with brine,
dried (MgSO.sub.4), concentrated and applied to a silica Bond Elut
Cartridge (5 g) in dichloromethane containing methanol. The
cartridge was eluted with dichloromethane, diethyl ether and ethyl
acetate to give the title compound (0.16 g), LCMS RT=3.49 min.
ii)
N.sup.2-[(3-{4-[(6-Iodohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N.sup.2-{-
[2-(trimethylsilyl)ethoxy]methyl}glycinamide compound with
N.sup.2-[(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N-2-{[2-(tr-
imethylsilyl)ethoxy]methyl}glycinamide (55:45)
[0622]
N.sup.2-[(3-Iodophenyl)sulfonyl]-N.sup.2-{[2-(trimethylsilyl)ethox-
y]methyl}glycinamide (0.16 g) was stirred with 6-bromohexyl
but-3-ynyl ether (0.086 g) in acetonitrile (2 ml) and
diisopropylethylamine (2 ml) under nitrogen for 10 min. Cuprous
iodide (0.01 g) and dichlorobis(triphenylphosphine)palladium (0.02
g) were added and the stirring continued for 2 h.
[0623] The solution was evaporated to dryness and applied to a Bond
Elut cartridge (5 g) in dichloromethane. The cartridge was eluted
with dichloromethane and diethyl ether to give the title compounds
(0.165 g), LCMS RT 3.93 min (bromide) and 4.02 min (iodide).
ii) 2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone
[0624] 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone
(Glaxo DE 3513885, 1985) (52 g) in DMF (300 ml) was treated with
sodium azide (12.24 g) and the mixture was stirred for 2 h at
20.degree. C. The reaction mixture was diluted with ethyl acetate
and washed with water and dried (MgSO.sub.4). The solvent was
removed under reduced pressure to give the title compound (39.11
g). TSP+ve 248(MH).sup.+.
iii)
(1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
[0625] R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (1M,
7.5 ml) was added to THF (75 ml) and the solution was diluted to
0.degree. C. Borane-THF complex (1M solution in THF, 125 ml) was
added and the mixture was stirred under nitrogen for 15 min. A
solution of
2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g)
in THF (250 ml) was added dropwise over 1.5 h at 5.degree. C. The
mixture was stirred for a further 1 h and then cautiously treated
with 2M HCl (100 ml). The reaction mixture was extracted with ether
and the organic layer was washed with 2M HCl, NaHCO.sub.3, brine,
dried (MgSO.sub.4). The solvent was removed by evaporation and the
residue was chromatographed on a Biotage column eluting with
diethyl ether-petrol (40-60.degree. C.) (1:9; 1:1) to give the
title compound (16.99 g). ES+ve 250 (MH).sup.+.
iv)
(1R)-2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
[0626] (1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
(16.99 g) was hydrogenated over 10% Pd--C (1 g) in ethanol (300
ml). The catalyst was collected by filtration, and washed with
ethanol. The combined washings were evaporated under reduced
pressure and the residue was triturated in diethyl ether to give
the title compound (5.86 g). The mother liquors were
chromatographed on a Biotage column eluting with
toluene:ethanol:aqueous ammonia (85:14:1) to give a further batch
of the title compound (5.99 g). LCMS RT=1.68 min, ES+ve 206
(MH-H.sub.2O).sup.+.
vi)
N.sup.2-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-h-
ydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N.sup.2-{[2-(trime-
thylsilyl)ethoxy]methyl}glycinamide
[0627] (1R)-2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
(0.134 g) was stirred with
N.sup.2-[(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N.sup.2-{[2--
(trimethylsilyl)ethoxy]methyl}glycinamide compound with
N.sup.2-[(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N.sup.2-{[2-
-(trimethylsilyl)ethoxy]methyl}glycinamide (55:45) (0.165 g) in DMF
(3 ml) for 4 days at 21.degree.. The mixture was evaporated to
dryness and applied to a silica Bond Elut Cartridge (5 g) in ethyl
acetate. This was eluted with ethyl acetate and then 10% methanol
in ethyl acetate to give the title compound (0.081 g) LCMS RT=3.04
min.
vii)
N.sup.2-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2--
hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N.sup.2-{[2-(trimethyl-
silyl)ethoxy]methyl}glycinamide
[0628]
N.sup.2-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N.sup.2-{[2-(t-
rimethylsilyl)ethoxy]methyl}glycinamide (0.09 g) was stirred with
platinum oxide (0.023 g) in ethanol (20 ml) under hydrogen for 3.5
h. The catalyst was filtered off with the aid of celite and the
filter cake was leached with ethanol. The combined filtrates were
evaporated to give the title compound (0.091 g) LCMS RT=3.10
min.
viii)
N.sup.2-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxnmethyl)ph-
enyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamide
acetate
[0629]
N.sup.2-[(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-
-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N.sup.2-{[2-(trimet-
hylsilyl)ethoxy]methyl}glycinamide (0.091 g) was stirred under a
reflux condenser at 80.degree. in acetic acid (2 ml) and water (1
ml) for 3.5 h. The solution was evaporated to dryness and
re-evaporated twice with methanol to give a gum. The residue was
dissolved in methanol and loaded onto two 20.times.20 cm
preparative silica gel coated plates (1 mm layer). The plates were
run in dichloromethane:ethanol:0.880 ammonia solution, 25:8:1 and
elution of the main band and evaporation gave a gum. This was
dissolved in acetic acid (2 ml) and evaporated to dryness and
re-evaporated with methanol to give the title compound (0.019 g)
LCMS RT=2.31 min, ES+ve 552 (MH).sup.+.
Example 50
6.alpha.,9.alpha.-Difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hyd-
roxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester Unsolvated Form 1 (a)
6.alpha.,9.alpha.-Difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid
[0630] A solution of 6.alpha.,9.alpha.-difluoro-11.beta.,
17.alpha.-dihydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-ca-
rbothioic acid (prepared in accordance with the procedure described
in GB 2088877B) (18 g, 43.64 mmol) in anhydrous dichloromethane
(200 ml) and triethylamine (15.94 ml, 114 mmol) was treated at
<5.degree. C. with a solution of 2-furoyl chloride (11.24 ml,
114 mmol) in anhydrous dichloromethane (100 ml) over approximately
40 min. The solution was stirred at <5.degree. C. for 30 min.
The resulting solid was collected by filtration, washed
successively with 3.5% aqueous sodium hydrogen carbonate solution,
water, 1M hydrochloric acid, and water and dried in vacuo at
60.degree. C. to give a cream coloured solid. The dichloromethane
filtrate was washed successively with 3.5% sodium hydrogen
carbonate solution, water, 1M hydrochloric acid, water, dried
(Na.sub.2SO.sub.4) and evaporated to give a cream coloured solid
which was combined with that isolated above. The combined solids
(26.9 g) were suspended in acetone (450 ml) and stirred.
Diethylamine (16.8 ml, 162 mmol) was added and the mixture stirred
at room temperature for 4.5 h. The mixture was concentrated and the
precipitate collected by filtration and washed with a little
acetone. The washings and filtrate were combined, concentrated and
loaded onto a silica gel Biotage column which was eluted with 24:1
chloroform:methanol. Fractions which contained the more polar
component were combined and evaporated to give a cream coloured
solid. This was combined with the solid isolated above and dried in
vacuo to give a pale beige coloured solid (19.7 g). This was
dissolved in warm water, the pH adjusted to 2 with concentrated
hydrochloric acid and the mixture extracted with ethyl acetate. The
organic extract was dried (Na.sub.2SO.sub.4) and evaporated to
give, after drying at 50.degree. C., the title compound as a cream
coloured solid (18.081 g, 82%): LCMS retention time 3.88 min, m/z
507 MH.sup.+, NMR .delta. (CDCl.sub.3) includes 7.61 (1H, m),
7.18-7.12 (2H, m), 6.52 (1H, dd, J 4, 2 Hz), 6.46 (1H, s), 6.41
(1H, dd, J 10, 2 Hz), 5.47 and 5.35 (1H, 2 m), 4.47 (1H, bd, J=9
Hz), 3.37 (1H, m), 1.55 (3H, s), 1.21 (3H, s), 1.06 (3H, d, J=7
Hz).
[0631] A suspension of the product of part (a) (2.5 g, 4.94 mmol)
was dissolved in anhydrous N,N-dimethylformamide (25 ml) and sodium
hydrogen carbonate (465 mg, 5.53 mmol) was added. The mixture was
stirred at -20.degree. C. and bromofluoromethane (0.77 ml, 6.37
mmol) was added and the mixture was stirred at -20.degree. C. for 2
h. Diethylamine (2.57 ml, 24.7 mmole) was added and the mixture
stirred at -20.degree. C. for 30 min. The mixture was added to 2M
hydrochloric acid (93 ml) and stirred for 30 min. Water (300 ml)
was added and the precipitate was collected by filtration, washed
with water and dried in vacuo at 50.degree. C. to give a white
solid which was recrystallised from acetone/water (to yield the
acetone solvate of
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic
acid S-fluoromethyl ester) and dried in vacuo at 50.degree. C. to
give the title compound (2.351 g, 88%): LCMS retention time 3.66
min, m/z 539 MH.sup.+, NMR .delta. (CDCl.sub.3) includes 7.60 (1H,
m), 7.18-7.11 (2H, m), 6.52 (1H, dd, J=4.2 Hz), 6.46 (1H, s), 6.41
(1H, dd, J 10, 2 Hz), 5.95 and 5.82 (2H dd, J 51, 9 Hz), 5.48 and
5.35 (1H, 2 m), 4.48 (1H, m), 3.48 (1H, m), 1.55 (3H, s), 1.16 (3H,
s), 1.06 (3H, d, J7 Hz).
Example 51
6.alpha.,9.alpha.-Difluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-[(4-
-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17.beta.-car-
bothioic acid S-fluoromethyl ester
[0632] Example 51 was prepared using a method analogous to that
described for Example 50: LCMS retention time 3.51 min, m/z 570
MH.sup.+
Biological Activity
[0633] The potencies of the aforementioned compounds were
determined using frog melanophores transfected with the human beta
2 adrenoreceptor. The cells were incubated with melatonin to induce
pigment aggregation. Pigment dispersal was induced by compounds
acting on the human beta 2 adrenoreceptor. The beta 2 agonist
activity of test compounds was assessed by their ability to induce
a change in light transmittance across a melanophore monolayer (a
consequence of pigment dispersal). At the human beta 2
adrenoreceptor, compounds of examples 1-49 had IC.sub.50 values
below 1 .mu.M.
[0634] Potency at other beta adrenoreceptor subtypes was determined
using chinese hamster ovary cells transfected with either the human
beta I adrenoreceptor or the human beta 3 adrenoreceptor. Agonist
activity was assessed by measuring changes in intracellular cyclic
AMP.
[0635] The application of which this description and claims forms
part may be used as a basis for priority in respect of any
subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described
herein. They may take the form of product, composition, process, or
use claims and may include, by way of example and without
limitation, the following claims:
* * * * *